Sample Output

Abbott-85499
Drug Metabolism Report No. 40
Overview of the Absorption, Distribution, Metabolism and

Excretion of Dexmedetomidine HCl (Abbott-85499.1) in
Animals
R&D/98/112
Author:
[Signature: Illegible] 03-12-98

Joseph M. Machinist, Ph.D.
Metabolism, Radiochemistry and Cellular Toxicity
Contributors:
Paulette Johnson, B.S., Samuel B. Thomas, M.S., Dean Hickman, Ph.D.,

Gondi N. Kumar, Ph.D., Gary A, Rotert, M.A.
Yu-hua Hui, Ph.D., Experimental Sciences
Peer Reviewed by:

Dean Hickman, Ph.D.
Approved and Submitted by:

Stanley A. Roberts, Ph.D., D.A.B.T.
Manager, Metabolism, Radiochemistry and Cellular Toxicity
Abbott Laboratories
Drug Metabolism. Abbott – 85499:40, R&D/98/112 i
5 NON-CLINICAL PHARMACOLOGY, TOXICOLOGY, AND ABSORPTION,

DISTRIBUTION, METABOLISM AND EXCRETION
5.3.2 Overview ................................................................................................................... 1

5.3.2.1 Introduction ............................................................................................. 1
5.3.2.2 Absorption and Pharmacokinetics ........................................................... 2
5.3.2.3 Protein Binding ........................................................................................ 3
5.3.2.4 Distribution .............................................................................................. 4
5.3.2.5 Metabolic Pathways ................................................................................. 6
5.3.2.6 Excretion .................................................................................................. 7
5.3.2.7 Human and Interspecies Comparison ...................................................... 8
5.3.3 Rats .......................................................................................................................... 11
5.3.3.1 Summary ................................................................................................ 11
5.3.3.2 Introduction ........................................................................................... 13
5.3.3.3 Absorption and Pharmacokinetics ......................................................... 13
5.3.3.4 Protein Binding ...................................................................................... 15
5.3.3.5 Distribution ............................................................................................ 15
5.3.3.6 Placental and Lacteal Transfer............................................................... 16
5.3.3.7 Metabolic Pathways ............................................................................... 17
5.3.3.8 Excretion ................................................................................................ 18
5.3.4 Rabbits .................................................................................................................... 19
5.3.5 Dogs ......................................................................................................................... 20
5.3.5.1 Summary ................................................................................................ 20
5.3.5.2 Introduction ........................................................................................... 21
5.3.5.3 Absorption and Pharmacokinetics ......................................................... 21
5.3.5.4 Protein Binding ...................................................................................... 23
5.3.5.6 Excretion ................................................................................................ 24
5.3.6 Humans ................................................................................................................... 25
5.3.6.1 Summary ................................................................................................ 25
5.3.6.2 Introduction ........................................................................................... 26
5.3.6.3 Dexmedetomidine and Plasma Metabolites ........................................... 27
5.3.6.4 Protein Binding ...................................................................................... 29
5.3.6.5 Distribution ............................................................................................ 29
Drug Metabolism. Abbott – 85499:40, R&D/98/112 ii
5.3.6.7 CYP-Mediated Metabolism ................................................................... 30
5.3.6.8 Excretion ................................................................................................ 31
5.3.7 Human and Interspecies Comparison .................................................................. 32
5.3.8 Chemistry................................................................................................................ 35
5.3.8.1 Synthesis of Radiolabeled Medetomidine ............................................. 35
5.3.8.2 Preparative Separation Dexmedetomidine............................................. 36
5.3.8.3 Assays for Dexmedetomidine ................................................................ 36
5.3.9 Tables ................................................................................ Error! Bookmark not defined.
Table 1. Summary of Dexmedetomidine Pharmacokinetic Data in Animals .................. 38
Table 2. Summary of Pharmacokinetic Parameters for Dexmedetomidine in

Rats .................................................................................................................... 39

Dogs ................................................................................................................... 40

Rabbits ............................................................................................................... 41
Table 5. Summary of [3H]Dexmedetomidine Metabolism in Animals and

Humans - Plasma Data ....................................................................................... 42
Table 6. Excretion Data for the [3H]Dexmedetomidine Dose in Animals and

Humans .............................................................................................................. 43
Table 7. Summary of Urinary Excretion of [3H]Dexmedetomidine and

Metabolites in Animals and Humans ................................................................. 44
Table 8. Summary of Fecal and Biliary Excretion of [3H]Dexmedetomidine

and Metabolites in Animals and Humans .......................................................... 45
Table 9. Summary of Pharmacokinetic and Metabolism Results in Rats Given

[3H]Dexmedetomidine - Plasma Data ................................................................ 46
Table 10. Distribution of Radioactivity in Tissues of Rats after an Intravenous

Dose of [3H]Dexmedetomidine.......................................................................... 47
Table 11. Summary of Metabolism Results in Rats Given

[3H]Dexmedetomidine - Urine Data† ................................................................. 48

[3H]Dexmedetomidine - Feces Data† ................................................................. 49
Drug Metabolism. Abbott – 85499:40, R&D/98/112 iii
[3H]Dexraedetomidine - Bile Data† ................................................................... 50
Table 14. Summary of Pharmacokinetic and Metabolism Results in Dogs Given

[3H]Dexmedetomidine - Plasma Data ................................................................ 51
Table 15. Summary of Metabolism Results in Dogs Given

[3H]Dexmedetomidine - Hour Urine Data ......................................................... 52
Table 16. Summary of Metabolism Results in Dogs Given

[3H]Dexmedetomidine - Feces Data ................................................................. 53
Table 17. Summary of Pharmacokinetic and Metabolism Results in Humans

Given [3H]Dexmedetomidine - Plasma Data ..................................................... 54

Given [3H]Dexmedetomidine - Urine Data ....................................................... 55

Given [3H]Dexmedetomidine - Feces Data........................................................ 56
5.3.10 Figures......................................................................... Error! Bookmark not defined.
Figure 1. Proposed Dexmedetomidine Metabolic Pathway ................................................. 57
5.3.11 Summaries of Individual Reports......................................................................... 58
5.3.11.1. Hui YH. Abbott-85499 Drug Metabolism Report No. 34 - Plasma
Concentrations of Dexmedetomidine Following Subcutaneous
Dosing in Rat (Protocol V96-557). Abbott Laboratories Division
46 Report No. R&D/97/617, January 1998. .......................................... 58
5.3.11.2 Hui YH. Abbott-85499 Drug Metabolism Report No. 32 - Plasma
Concentrations of Dexmedetomidine Following a Single IV or IM
Dose in Dog (Protocol V96-556). Abbott Laboratories Division 46
Report No. R&D/97/615, January 1998. ............................................... 61
5.3.11.3 Hui YH, Marsh K. Abbott-85499 Drug Metabolism Report No. 5 -
Plasma Concentrations of Abbott-85499 (Dexmedetomidine)
following Repeat Intrathecal Administration in Dog (Protocol
TB95-224). Abbott Laboratories Division 46 Report No.
R&D/96/074, April 1996. ...................................................................... 64
Concentrations of Dexmedetomidine Following Intravenous
Dosing in Rabbit (Protocol V96-558). Abbott Laboratories
Division 46 Report No. R&D/97/616, January 1998............................. 68
5.3.11.5 Mayer MD, Machinist JM. Abbott-85499 Drug Metabolism Report
No. 6 - Metabolism and Excretion of [3H]Dexmedetomidine
(Abbott-85499) in Rats (Protocol V95-031). Abbott Laboratories
Division 46 Report No. R&D/96/233, March 1996............................... 70
Drug Metabolism. Abbott – 85499:40, R&D/98/112 iv
5.3.11.6 Salonen JS. (October 1988), Orion-Farmos Study Report BA-88-
04 - Pharmacokinetics of 3H-Labelled Dexmedetomidine in the
Rat .......................................................................................................... 72
No. 19 - Metabolism and Disposition of [3H]Abbott-85499.1
(Dexmedetomidine-HCl) Following Subcutaneous and Intravenous
Administration to Dogs (Protocol V96-020).Abbott Laboratories
Division 46 Report No. R&D/97/291, May 1997. ................................. 73
No. 26 - Phase I Study of the Metabolism and Excretion of
[3H]Dexmedetomidine•HCl (Abbott-85499.1) in Normal Male
Subjects (Protocol Dex-96-018). Abbott Laboratories Division 46
Report No. R&D/97/457, September 1997............................................ 74
5.3.11.9 Kukulka MJ, Machinist JM. Abbott-85499 Drug Metabolism
Report No. 8 - In Vitro Protein Binding of [3H] Abbott-85499
(Dexmedetomidine) in Mouse, Rat, Dog, Monkey and Human
Plasma (Protocol V96-004). Abbott Laboratories Division 46
Report No. R&D/96/320, July 1996. ..................................................... 76
Report No. 20 - In Vitro Binding of [3H] Abbott-85499
(Dexmedetomidine) to Human Serum Albumin and α1-Acid
Glycoprotein (Protocol 96-011). Abbott Laboratories Division 46
Report No. R&D/97/338, June 1997. .................................................... 77
5.3.11.11 Machinist JM. Abbott-85499 Drug Metabolism Report No.29 -
Protein Binding Interactions Between Abbott-85499-3H
(Dexmedetomidine) and Selected Other Drugs in Human Plasma
(Protocol V97-034). Abbott Laboratories Division 46 Report No.
R&D/97/525, September 1997. ............................................................. 78
5.3.11.12 Machinist JM, Johnson MK. Abbott-85499 Drug Metabolism
Report No. 30 - Effect of Abbott-85499 (Dexmedetomidine) on the
Protein Binding of Selected Other Drugs in Human Plasma
R&D/97/526, September 1997. ............................................................. 78
Report No. 22 - In Vitro Determination of Human Red Cell
Binding of Abbott-85499-3H (Dexmedetomidine) (Protocol V97-
026). Abbott Laboratories Division 46 Report No. R&D/97/371,
September 1997. .................................................................................... 79
5.3.11.14 Machinist JM. Abbott-85499 Drug Metabolism Report No.17 -
Tissue Distribution of Radioactivity in Rats following a Single
Intravenous 0.02 mg/kg Dose of [3H]Dexmedetomidine-HCl
(Abbott-85499.1). Abbott Laboratories Division 46 Report No.
R&D/96/720, January 1997. .................................................................. 80
Drug Metabolism. Abbott – 85499:40, R&D/98/112 v
5.3.11.15 Machinist JM. Abbott-85499 Drug Metabolism Report No. 31 -
Lacteal Excretion and Fetal Tissue Distribution of Radioactivity
Following a Single Subcutaneous Dose of
[3H]Dexmedetomidine•HCl (Abbott-85499.1) in the Rat (Study
No. Covance 6161-175). Abbott Laboratories Division 46 Report
No. R&D/97/565, September 1997........................................................ 81
5.3.11.16 Salonen JS. Tissue-Specificity of Hydroxylation and N-
Methylation of Arylalkylimidazoles. Pharmacol Toxicol
1991;69:1-4. ........................................................................................... 82
No. 28 - Metabolism of [3H]Dexmedetomidine,
[3H]Levomedetomidine and [3H]Medetomidine by Precision- Cut
Rat Liver Slices. Abbott Laboratories Division 46 Report No.
R&D/97/504, November 1997............................................................... 83
No. 25 - Metabolism of [3H]Dexmedetomidine,
Dog Liver Slices. Abbott Laboratories Division 46 Report No.
R&D/97/454, August 1997. ................................................................... 84
5.3.11.19 Salonen JS. (January 1996). Pharmacokinetics and Metabolic
Profiling of 3H-Labeled Dexmedetomidine in Healthy Male
Volunteers. Metabolic Profile of 3H-Dexmedetomidine in Human
Urine. Study BA-91-04 (PBR-910208-4), Pharma-Bio Research
International. Supplement 2, Biotransformation Report, Orion-
Farmos DNO JSS95051......................................................................... 85
No. 23 - Metabolism of [3H] Dexmedetomidine,
Human Liver Slices. Abbott Laboratories Division 46 Report No.
R&D/97/389, July 1997 ......................................................................... 85
5.3.11.21 Hickman D, Kumar G. Abbott-85499 Drug Metabolism Report
No. 36 - Identification of Cytochrome P450 Isoforms Involved in
the Oxidative Metabolism of Dexmedetomidine (Abbott-85499)
and the Effect of Dexmedetomidine on Cytochrome P450-
Mediated Monooxygenase Activities. Abbott Laboratories
Division 46 Report No. R&D/97/757, January 1998............................. 87
5.3.11.22 Salonen JS, Eloranta M. Biotransformation of Medetomidine in the
Rat. Xenobiotica 1990;20:471-480. ....................................................... 89
No. 27 - Conversion of [3H]Dexmedetomidine to [3H]
Levomedetomidine in Male Subjects Following a 2 µg/Kg Infusion
of [3H]Dexmedetomidine•HCl. Abbott Laboratories Division 46
Report No. R&D/97/458, August 1997. ................................................ 90
Drug Metabolism. Abbott – 85499:40, R&D/98/112 vi
5.3.11.24 Pelkonen O, Puurunen J, Arvela P, Lammintausta R. Comparative
Effects of Medetomidine Enantiomers on In Vitro and In Vivo
Microsomal Drug Metabolism. Pharmacol Toxicol 1991;69:189-
194. ........................................................................................................ 90
5.3.11.25 Rodrigues AD. Abbott-85499 Drug Metabolism Report No.13-
The In Vitro Interaction of Dexmedetomidine with Human Liver
Microsomal Cytochrome P450 2D6 (CYP2D6). Abbott
Laboratories Division 46 Report No. R&D/96/557, August 1996. ....... 91
5.3.11.26 Kharasch ED, Hill HF, Eddy AC. Influence of Dexmedetomidine
and Clonidine on Human Liver Microsomal Alfentanil
Metabolism. Anesthesiology 1991;75:520-524...................................... 92
5.3.11.27 Kharasch ED, Herrmann S, Labroo R. Ketamine as a Probe for
Medetomidine Stereoisomer Inhibition of Human Liver
Microsomal Drug Metabolism. Anesthesiology 1992;77:1208-
1214. ...................................................................................................... 93
5.3.11.28 Virtanen R. Orion-Pharma Research Report - The Effects of
Dexmedetomidine N-Glucuronides on Alpha-2 Adrenoceptors In
Vitro and In Vivo. Study No. CNS97122100010, August 1997. ........... 94
5.3.11.29 Aantaa R, Kallio A, Virtanen R. Dexmedetomidine, a Novel α2-
Adrenergic Agonist. A Review of its Pharmacodynamic
Characteristics. Drugs of the Future. 1993; 18(l):49-56. ....................... 94
No. 11 - Metabolism and Excretion of [3H]Dexmedetomidine
Following Intravenous or Subcutaneous Administration to
Chronically Bile Duct Cannulated Rats (Protocol V96-014).
Abbott Laboratories Division 46 Report No. R&D/96/443, July
1996. ...................................................................................................... 95
5.3.11.31 Schwietert HR, Leeuwenkamp OR, van Lier JJ, Mensink CK,
Sollie FAE, Jonkman JHG. Pharmacokinetics and Metabolic
Profiling of 3H-Labeled Dexmedetomidine in Healthy Male
Volunteers. Biometrical Report. Study BA-91-04 (PBR-910208-4),
Pharma-Bio Research International B.V., March 1994. ........................ 96
5.3.11.32 Thomas SB. Abbott-85499 Drug Metabolism Report No. 2 -
Preparative Separation and Analysis of the Tritiated Dextro and
Levo Enantiomers of Medetomidine. Abbott Laboratories Division
46 Report No. R&D/95/949, March 1996. ............................................ 98
5.3.11.33 Hui YH. Abbott-85499 Drug Metabolism Report No. 4 - A GC-
MS Method for the Quantitation of Dexmedetomidine (Abbott-
85499) in Plasma. Abbott Laboratories Division 46 Report No.
R&D/96/073, May 1996. ....................................................................... 98
5.3.12 References ............................................................................................................. 100
Drug Metabolism. Abbott – 85499:40, R&D/98/112 1
5.3.2 Overview
5.3.2.1 Introduction
Dexmedetomidine-HCl (Abbott-85499.1) is a specific and selective α2-adrenoreceptor

agonist with potential utility in clinical anesthesia and ICU sedation for both its sedative and
sympatholytic properties. The drug has been licensed by Abbott Laboratories from Orion-
Pharma. Although the drug is intended to be used intravenously in humans, pharmacokinetic
studies using alternative routes of administration (intramuscular, subcutaneous or intrathecal)
have been conducted in rats and dogs to provide absorption and exposure estimates in
support of toxicology studies. Pharmacokinetic studies in rabbits have been conducted only
by the intravenous route. The absorption, distribution, metabolism and excretion of
dexmedetomidine were also investigated in rats, dogs and humans. In all studies, the drug
was administered as the hydrochloride salt, but all plasma data are expressed in terms of the
free base. The doses used in these studies ranged from those which approximate therapeutic
doses in humans to those used in subchronic or chronic toxicity studies in animals. All of the
metabolism studies sponsored by Abbott were done using [3H]dexmedetomidine labeled with
tritium at the bridge methyl position. In vitro metabolism studies were also conducted using
human liver microsomes and human B-lymphoblastoid microsomes containing cDNA-
expressed CYP proteins, as well as liver slices from rats, dogs and humans. Rats or tissues
from rats were used in a number of specialized studies investigating tissue distribution as
well as placental and lacteal transfer. In vitro protein binding was determined in dog, rat,
mouse, monkey and human plasma, while protein binding interactions between
dexmedetomidine and a number of drugs were studied in human plasma. Metabolic patterns
in biological samples were determined using high pressure liquid chromatography in
conjunction with a radioactivity flow detector.
The pharmacokinetic data for dexmedetomidine and its metabolites in animals are
summarized in Tables 1-5 and the metabolism and excretion data are summarized in Tables
6-8. More detailed tabulations of the data are given in Tables 9-13 for rats, Tables 14-16 for
dogs, and Tables 17-19 for humans. A proposed dexmedetomidine metabolic pathway is
illustrated in Figure 1.
5.3.2.2 Absorption and Pharmacokinetics
Subcutaneous doses of dexmedetomidine in rats and intramuscular doses of the drug in dogs
were rapidly absorbed, with peak times of parent drug occurring within one hour (Tables 1-
3).1,2 In both species, greater than proportional increases in both peak plasma concentrations
and AUC values as the dose was increased suggested that the pharmacokinetics were non-
linear. Plasma AUC values after an intramuscular dose of the drug to dogs averaged 25.66
ng•h/mL (50 µg/kg) and 428.4 ng•h/mL (250 µg/kg), respectively. Comparison of the AUCs
after a single intravenous and intramuscular 50 µg/kg dose to dogs provided a mean
bioavailability estimate of about 60% for the intramuscular dose. The mean plasma
elimination half-life of dexmedetomidine in dogs ranged from 0.68 to 1.31 hours after
intravenous and intramuscular administration. Following intrathecal administration to dogs,
the mean AUC values averaged 0.007 (0.2 µg/kg), 0.124 (1.2 µg/kg), and 1.80 ng•h/mL (8.0
µg/kg) on the first day of dosing.3 These values did not change appreciably with multiple
dosing for 22 days, suggesting that the drug did not accumulate under these conditions
(Table 3). Plasma elimination half-lives after intrathecal doses averaged 0.64 and 0.86 hours.
After a single subcutaneous dose of dexmedetomidine to rats, AUC values averaged 3.4 (20
µg/kg), 33.9 (100 µg/kg), and 263.1 ng•h/mL (500 µg/kg) (Tables 1-2).1 The terminal
elimination half-life of parent drug in rats was estimated to be about 2 hours. A single
intravenous 96 µg/kg dose of dexmedetomidine to female rabbits afforded a mean exposure
(AUC) value of 40.7 ng•h/mL and a terminal elimination half-life of 1.83 hours (Table 4).4
Total radioactivity appeared to be well absorbed following 20 µg/kg subcutaneous doses of

[3H]dexmedetomidine to rats and dogs (Tables 5,9,14).5,6,7 Compared to a corresponding
intravenous dose, bioavailability of parent drug after a subcutaneous dose to dogs was
quantitative; reliable estimates of bioavailability were not obtained in rats. After either route
of dosing, major identified metabolites of dexmedetomidine in rat and dog plasma consisted
of the 3-hydroxy metabolite (OH) and its subsequent biotransformation products, the
carboxylic acid metabolite (COOH), and the glucuronide (G-OH) and sulfate (SO3OH)
conjugates (Figure 1).5,6,7 The mean AUC values for these metabolites ranged from 0.46 to
8.37 ng Eq•h/mL and represented about 2 to 12% of the AUC for total plasma
radioactivity.5,7 Major metabolites in human plasma were two N-glucuronides of parent drug
(G-Dex-1 and G-Dex-2) which collectively had an AUC value of 9.17 ng Eq•h/mL and
represented about 41% of the AUC for plasma total radioactivity (Tables 5,17).8 The
glucuronide of the N-methyl hydroxy metabolite (G-N-Me-OH; AUC 4.56 ng Eq•h/mL) and
an additional hydroxylated metabolite, H-3 (AUC 3.48 ng Eq•h/mL) were also detected in
human plasma and represented approximately 20 and 16% of the AUC for total plasma
radioactivity, respectively.
5.3.2.3 Protein Binding
The in vitro plasma protein binding of [3H]dexmedetomidine was determined with an

ultrafiltration technique.9 At concentrations ranging from 0.85 to 85 ng base/mL, the protein
binding of [3H]dexmedetomidine averaged 93.72% in human plasma, 94.89% in mouse
plasma, 88.16% in rat plasma, 84.59% in monkey plasma and 92.58% in dog plasma.
[3H]Dexmedetomidine was bound to physiological concentrations of both human serum

albumin (HSA) and α1-acid glycoprotein (α1-AGP).10 The binding of [3H]dexmedetomidine
to HSA (40 mg/mL) averaged 80.75% and was concentration independent from 0.85 to 85
ng base/mL. The binding of the tritiated drug to α1-AGP (0.8 mg/mL) averaged 63.96%
bound over the same drug concentration range. Since the binding of the drug to either protein
was less than that in human plasma, other plasma proteins may be also involved.
In vitro protein binding interaction studies in human plasma between [3H]dexmedetomidine

(0.6 ng base/mL) and fentanyl, ketorolac, theophylline, digoxin, and lidocaine were
conducted.11 The [3H]dexmedetomidine plasma protein binding was only slightly decreased
(0.05 to 0.92%) by addition of any of these compounds. Moreover, the human plasma
protein binding of radiolabeled phenytoin, warfarin, ibuprofen, propranolol, theophylline and
digoxin was not appreciably changed in the presence of dexmedetomidine (0.6 ng
base/mL).12
5.3.2.4 Distribution
Red Blood Cell Binding
In vitro studies with [3H]dexmedetomidine at concentrations of 0.5 and 5 ng base/mL

showed that the binding of dexmedetomidine to human red blood cells is low.13 Over the
concentration range studied, the fraction of drug bound to red cells (frbc) averaged 0.183, the
red blood cell to plasma concentration ratio (Crbc/Cp) averaged 0.325 and the whole blood to
plasma concentration ratio (Cblood/Cp) averaged 0.723 for both sexes.
Tissue Distribution In Rat
The distribution of radioactivity was studied in tissues of male and female Sprague Dawley
rats given a 20 µg/kg intravenous dose of [3H]dexmedetomidine (Table 10).14 Drug-related
radioactivity was rapidly and widely distributed throughout the animal body, with highest
mean concentrations in blood, plasma and selected tissues occurring from 0.25 to 12 hours
post-dose. Cmax values in plasma were 2.9 and 4.5 ng Eq/mL in males and females,
respectively. The levels of radioactivity in the tissues exceeded those in plasma on at least
one collection point for all tissues except bone. Mean peak concentrations of radioactivity
were highest in the liver, adrenals, lungs, kidneys, small and large intestine (including
contents), stomach (including contents) and pancreas, with values ranging from 62.3 to 382.3
ng Eq base/g. Tissues not listed in the table contained less than 34 ng Eq/g at all sampling
times. The mean peak concentration of radioactivity in the brain was about 6-fold greater
than that in plasma.
Concentrations of radioactivity declined with time such that after 72 hours the levels in the
plasma and most tissues had decreased to about 0.1 to 5% of their respective peak values.
Elimination from the adrenals was slower and after 72 hours the concentrations of
radioactivity (23.8 and 49.3 ng Eq base/g; M/F) were about 12 to 13% of their respective
peak values and 222 to 1050 times greater than the corresponding plasma concentrations.
Similar findings were reported following a 40 µg/kg subcutaneous dose of the tritiated drug
to rats.6
The highest concentrations of radioactivity in male Long Evans rats were found in the liver
(241 ng Eq/g), kidneys (183 ng Eq/g) and eyes (without lens; 108 ng Eq/g) at 0.25 to 1 hour
after dosing (data not shown).14 Although levels of radioactivity in pigmented (7.23 ng Eq/g)
and non-pigmented (6.92 ng Eq/g) skin were comparable, the mean maximal level in
pigmented eyes was almost 30-fold greater than that in non-pigmented eyes of male Sprague
Dawley rats (3.89 ng Eq/g), suggesting some binding of radioactivity to melanin.
Placental and Lacteal Transfer
After a subcutaneous 15 µg/kg dose of [3H]dexmedetomidine to 18 day gravid rats,

radioactivity crossed the placental barrier and was distributed in maternal and fetal tissues15
The highest mean concentrations of radioactivity in maternal and fetal tissues occurred at 1
hour post-dose for all tissues collected, except the maternal adrenal glands, amniotic fluid,
fetal blood and fetal kidneys which reached maximal levels at 8 hours.
The highest maternal levels (ng Eq base/g) were observed in the adrenals (275.73), lungs
(187.77), kidneys (62.08) and ovaries (26.47). The highest levels in the fetus were found in
blood (7.16), liver (5.13) and kidneys (4.78). The concentrations of radioactivity in blood,
plasma and maternal and fetal tissues declined over 72 hours to levels which were 0.15 to
38% of the mean peak values. Radioactivity was below the limit of detection in the maternal
brain, maternal heart, fetal heart and fetal kidneys at 72 hours post-dose.
Following administration of a subcutaneous 15 µg/kg dose of [3H]dexmedetoraidine to

lactating rats, total radioactivity was distributed into the milk of dams and reached a
maximum mean concentration at 4 hours (1.57 ng Eq base/mL).15 Thereafter, levels of
radioactivity in milk decreased to non-detectable levels at 72 hours. The milk to plasma
concentration ratio was less than 1 at all collection time points (about 0.48 to 0.87) indicating
that radioactivity did not accumulate in the milk.
5.3.2.5 Metabolic Pathways
Data from in vivo and in vitro studies indicate that dexmedetomidine was metabolized by
Phase I and Phase II reactions (Figure 1)5-8,16-21 Generally, the metabolic pathways consisted
of 1) an apparent cytochrome P450 (CYP)-mediated hydroxylation at the 3-position and
hydroxylation at the methyl position on the methylene bridge to form the OH and H-3
metabolites, respectively, 2) N-methylation to produce the N-methyl metabolite (N-Me) and
3) direct conjugation of parent drug to form two N-glucuronides, G-Dex-1 and G-Dex-2. In
rats, the OH metabolite can undergo secondary oxidation to produce the carboxylic acid
derivative (COOH) or be further metabolized to the O-glucuronide (G-OH), sulfate (SO3OH)
or glutathione (GS-OH) conjugates,5,6,17 in a manner previously reported for racemic
medetomidine.22 The GS-OH conjugate was subsequently metabolized in the liver and
excreted into the urine as the mercapturic acid conjugate (M-OH). Comparable pathways for
the OH metabolite were found in dogs and humans, but the SO3OH conjugate was apparently
not formed by humans while the M-OH metabolite was not detected in either species.7,8
Similarly, the N-Me metabolite can be N-demethylated to regenerate parent drug, or
converted to its corresponding 3-hydroxy derivative (N-Me-OH) which can be subsequently
metabolized to the carboxylic acid (N-Me-COOH) or the glucuronide (G-N-Me-OH). Direct
N-glucuronidation of parent drug to produce G-Dex-1 and G-Dex-2 appears to be a
significant pathway only in humans.8 Chiral inversion of dexmedetomidine to its inactive
levo-enantiomer was found to be of minimal significance in humans.23
The NADPH-dependent oxidative metabolism of [3H]dexmedetomidine was also examined

using suitably fortified human liver microsomes and human B-lymphoblastoid microsomes
containing cDNA-expressed cytochrome P450s (CYP).21 Two oxidative metabolites (OH
and H-3) were detected (Figure 1), both of which have been found in plasma samples from a
previous study with [3H]dexmedetomidine in humans and dogs.7,8 Data from human
microsomes, purified CYP enzymes and CYP-selective inhibitors suggest that the formation
of OH and H-3 is mediated largely by CYP2A6, although other CYP forms (CYP1A2,
CYP2E1, CYP2D6 and CYP2C19) may also be involved.21,24 These findings are consistent
with those which demonstrated dexmedetomidine to be a broad-spectrum inhibitor of the
metabolism of a number of CYP-selective substrates.24-27
In vitro, it appears that G-Dex-1 and G-Dex-2 exhibit characteristics of weak pre-synaptic
agonists in both the rat vas deferens and guinea pig ileum assays, being one to two orders of
magnitude less potent than parent drug.28 However, no central or peripheral α2-agonist
activity was found in vivo (mydriasis model), ostensibly because these glucuronides, which
are resistant to hydrolysis, could not penetrate the central nervous system and contribute to
the pharmacological activity. The levo-enantiomer as well as the N-methylated and OH, G-
OH and COOH metabolites are apparently devoid of α2-receptor activity, 16,22,29
5.3.2.6 Excretion
Both urinary and fecal excretion are routes of elimination for dexmedetomidine and its
metabolites from the body (Table 6). Following a 20 µg/kg intravenous or subcutaneous dose
of [3H]dexmedetomidine to rats (M+F), an average of about 65 and 50% of the dose was
found in the urine (including cagewash), while 34 and 48% was recovered in the feces,
respectively.5 Urinary excretion in female rats appeared to be greater than that seen in males.
Biliary secretion also appears to be a major route of elimination in rats of both sexes, since
about 45 to 52% of an intravenous or subcutaneous 20 µg/kg dose was recovered in the bile
after 24 hours.30 After identical doses of radiolabeled dexmedetomidine to male and female
beagle dogs, approximately 82 to 84% of the dose was excreted into the urine (including
cagewash), while about 13% was recovered in the feces.7 No sex related differences in
excretion were observed. Urinary excretion of radioactivity was predominant in male human
subjects after a 2 µg/kg infusion of [3H]dexmedetomidine, with 89 to 95% of the dose being
recovered in the urine; fecal excretion accounted for about 4 to 6% of the dose.8,31 Based on
urinary tritiated water calculations, less than 1% of the dose was converted into tritiated
water in all species.
Less than 1% of unchanged parent drug was recovered in the mine from all species,
indicating extensive metabolism (Tables 7, 11, 15, 18). Major metabolites in rat urine were
OH, COOH, G-OH, SO3OH and M-OH (about 2 to 9% of the dose), with the SO3OH and
M-OH metabolites predominating in females.5 With the exception of the M-OH compound,
these same metabolites were also found in dog urine (about I to 15% of the dose); sex-related
differences in metabolism were not observed.7 Urine from human male subjects contained
the COOH, OH, G-OH metabolites (about 1 to 8% of the dose), but the M-OH and SO3OH
metabolites were not detected.8 Major urinary metabolites in humans which were not
detected in urine from rats or dogs include G-Dex-1 and G-Dex-2 (19.56 and 14.43% of the
dose), as well as G-N-Me-OH and N-Me-COOH, which represented 14.51 and 3.76% of the
dose, respectively. Approximately 30 to 50% of the urinary metabolites from the species
studied have not been identified.
Generally, the patterns of fecal metabolites for each species were comparable to the
respective urinary metabolite profiles (Tables 8, 12, 16, 19). The OH and COOH metabolites
were found in rat, dog and human feces (0.18 to 5.77% of the dose). The SO3OH component
was also detected in rat and dog feces (0.24 to 3.04% of the dose) but not in human feces.
The G-OH metabolite (0.04 to 3.64% of the dose) was found only in rats and humans. Levels
of unchanged dexmedetomidine, G-Dex-1 and G-Dex-2 were not detected in rat and dog
feces and ranged from 0.01 to 0.06% of the dose in human feces. The major metabolite in rat
bile was the G-OH conjugate which represented about 15% of a 20 µg/kg intravenous or
subcutaneous dose of [3H]dexmedetomidine (Table 13).30 The glutathione conjugate of the
OH metabolite (GS-OH) as well as M-OH were also detected, accounting for 0.26 to 3.73%
of the dose. Lesser quantities of the COOH and SO3OH metabolites were also found. More
than 50% of the biliary and fecal metabolites have not been characterized.
5.3.2.7 Human and Interspecies Comparison
In rats, dogs and humans, intravenous and/or subcutaneous doses of [3H]dexmedetomidine

are eliminated by extensive metabolism and excreted largely into the urine. In humans and
dogs about 80 to 90% of the dose is found in the urine, while 5 to 13% is recovered in the
feces. Urinary excretion is somewhat less in rats (50 to 65%), with 34 to 48% of the dose
being excreted in the feces, primarily via the bile. Plasma protein binding was generally
comparable among species, averaging 88.16% in rats, 92.58% in dogs and 93.72% in
humans.
Under the experimental conditions described, dexmedetomidine metabolic pathways were

found to be species-dependent. Similarities in the patterns of identified plasma and urinary
metabolites were found in rats and dogs, but the patterns were unlike those found in humans,
suggesting that neither species represents an ideal model for the known metabolism of
dexmedetomidine in man. Metabolites common to each species have been detected or
inferred, but a major metabolic difference was the relative inability of rats and dogs to form
the G-Dex-1 and G-Dex-2 glucuronides. For example, the major metabolic pathway in rats
was an apparently CYP-driven hydroxylation (oxidation) to form the OH metabolite. All
other metabolites found represented further biotransformation products of the OH metabolite
(COOH, G-OH, SO3OH, GS-OH and M-OH). Collectively, exposure to this group of
metabolites in rats accounted for an average of about 37% of the AUC for plasma
radioactivity, 56% of the total urinary radioactivity and 45% of the radioactivity in bile. The
M-OH metabolite was found only in rat urine and not the urine from dogs or humans. No
evidence of a significant direct N-glucuronidation or N-methylation pathway was obtained
from in vivo or in vitro studies in rats. Rat kidney cytosol was shown to N-methylate
dexmedetomidine in vitro, but the system was of low affinity and low capacity and believed
not to be quantitatively important in the metabolism of the drug. This may explain the lack of
N-Me or related metabolites in rats and rat liver slices. The H-3 metabolite, which is formed
by hydroxylation of [3H]dexmedetomidine on the bridge methyl group, was not found in
biological samples from rats. Since the tritium label is located on the bridge methyl group,
formation of H-3 results in the partial loss of the tritium label with the subsequent formation
of tritiated water. The presence of tritiated water in rat plasma samples implies that H-3 was
also formed in this species, but may have been further metabolized and excreted as an
unidentified metabolite. It was estimated that less than 1 % of the dose was converted to
tritiated water in rats, dogs and humans. If it is assumed that all of the tritiated water is a
product of H-3 formation, this pathway was not a major contributor to the total metabolism
of dexmedetomidine in all species studied.
Relative Dexmedetomidine Pathways

Pathway Rat Dog Human
OH ++++ ++++ ++
GS-OH + ± ±
N-Me ± +++* ++
G-Dex-1/2 ± ± ++++
* = in vitro dog liver slices
Except for the lack of the GS-OH and M-OH metabolites, results from in vivo studies have
shown the hydroxylation pathway (OH) is ostensibly the predominant metabolic route in
dogs. In dogs, the OH, COOH, G-OH and SO3OH metabolites represented 17 to 49% of the
total radioactivity in plasma and urine. Although detectable levels of the N-Me metabolite or
known related metabolites were not found in vivo, in vitro studies have shown that about
50% of the metabolites formed after incubation of tritiated dexmedetomidine with dog liver
slices represent the N-Me or related compounds. A plausible explanation may be that the N-
Me metabolite formed in vivo was N-demethylated to regenerate parent drug which was then
metabolized to the OH, COOH, G-OH and SO3OH metabolites. As noted previously in rats,
formation of the H-3 metabolite in dogs was inferred from the presence of tritiated water in
plasma samples. Direct N-glucuronidation of parent drug does not appear to be a dominant
pathway in dogs.
Prominent metabolic pathways in humans were N-glucuronidation (G-Dex-1 and G-Dex-2)

and N-methylation (N-Me, N-Me-COOH, G-N-Me-OH) which accounted for about 41 and
21% of the plasma radioactivity and 36 and 19.5% of the total urinary activity, respectively.
The 3-hydroxylation pathway (OH, COOH, G-OH) was somewhat less in humans,
contributing about 5 and 15% of the plasma and urinary radioactivity, respectively. The H-3
metabolite was detected only in human plasma and accounted for about 16% of the AUC for
total plasma radioactivity. The absence of detectable levels of H-3 in human urine supports
the concept that it may have been subjected to further metabolism and excreted into the urine
as an unidentified metabolite. The dose of [3H] dexmedetomidine in the human study (2
µg/kg) was 10-fold lower than that used in the animal studies (20 µg/kg). It is possible that
the pattern of metabolites in humans at much higher doses may shift due to saturation of one
or more lower capacity pathways; saturation of the high capacity glucuronidation pathway,
however, seems unlikely.
A considerable number of metabolites in the urine from all species have not been
characterized. These components may arise from different routes of metabolism, including
hydroxylation of parent drug or the N-Me metabolite on other portions of the molecule
(aromatic) followed by conjugation , or possibly by other non-CYP mediated reactions.
5.3.3 Rats
5.3.3.1 Summary
Single doses of dexmedetomidine were rapidly absorbed from 20, 100 and 500 µg/kg
subcutaneous doses to rats, with peak plasma levels occurring within one hour.1 Cmax and
AUC values increased with increasing doses in a greater than proportional manner,
indicating that the pharmacokinetics were non-linear. Cmax concentrations (M+F) averaged
1.29, 10.65 and 71.59 ng/mL, respectively, while exposure values (AUCs) averaged 3.4, 33.8
and 263.1 ng•h/mL in the same animals. The terminal elimination half-lives for parent drug
were comparable in all treatment groups, averaging about 2 hours.
A 20 µg/kg intravenous or subcutaneous dose of [3H]dexmedetomidine was well absorbed in

rats. Tentatively identified circulating metabolites consisted of the hydroxy metabolite (OH),
the carboxylic acid metabolite (COOH), and the glucuronide (G-OH) and sulfate (SO3OH)
conjugates of the OH metabolite.5 Unidentified metabolites were also detected. The plasma
protein binding of [3H]dexmedetomidme averaged 88.16% in rat plasma.9
Drug-related radioactivity was rapidly and widely distributed throughout the body of
Sprague Dawley rats following a 20 µg/kg intravenous dose of the tritiated drug.14 The
highest mean concentrations in blood, plasma and selected tissues occurring from 0.25 to 12
hours post-dose. Levels of radioactivity in the tissues exceeded those in plasma on at least
one collection point for all tissues except bone. Cmax values in plasma were 2.9 and 4.5 ng
Eq/mL in males and females, respectively. Mean peak concentrations of radioactivity were
highest in the liver, adrenals, lungs, kidneys, small and large intestine (including contents),
stomach (including contents) and pancreas, with values ranging from 62.3 to 382.3 ng Eq
base/g. All other collected tissues contained less than 34 ng Eq/g at all sampling times. The
mean peak concentration of radioactivity in the brain was at about five- to seven-fold greater
than that in plasma. Concentrations of radioactivity declined with time such that after 72
hours levels in the plasma and most tissues had decreased to about 0.1 to 5% of their
respective peak values. Elimination from the adrenals was slower and after 72 hours
concentrations of radioactivity were about 12 to 13% of their respective peak values and 222
to 1050 times greater than the corresponding plasma concentrations. A similar distribution of
radioactivity was reported following a 40 µg/kg subcutaneous dose of the tritiated drug to
rats.6
Although concentrations of radioactivity in pigmented (7.23 ng Eq/g) and non-pigmented

(6.92 ng Eq/g) skin of Long Evans rats were comparable, mean maximal levels in pigmented
eyes was about 30-fold greater than that in non-pigmented eyes of male Sprague Dawley
rats, suggesting some binding of radioactivity to melanin.
After a subcutaneous 15 µg/kg dose of [3H]dexmedetomidine to an 18 day gravid rat,

radioactivity crossed the placental barrier and was distributed in maternal and fetal tissues.15
Following an identical dose of [3H]dexmedetomidine to lactating rats, total radioactivity was
extensively distributed in the milk of dams, but the mean levels did not exceed those in
plasma nor did the radioactivity appear to persist longer in milk- than in plasma.15
Dexmedetomidine is extensively metabolized in rats primarily by oxidative and conjugative

mechanisms.5,6,16,17 The major identified pathway involves hydroxylation to form the OH
metabolite, with secondary metabolism of the OH component to form the COOH,
glucuronide (G-OH), sulfate (SO3OH), glutathione (GS-OH) and subsequent mercapturate
(M-OH) conjugates. N-methylation was also detected in rat kidney cytosol.16 The levo-
enantiomer as well as the N-methylated, OH, and COOH metabolites are apparently devoid
of α2-receptor activity.l6,22,29
Both urinary and fecal excretion were involved in the elimination of [3H]dexmedetomidine
from rats.5,6 Following intravenous or subcutaneous 20 µg/kg doses, an average of about 65
and 50% of the dose was recovered in the urine (including cagewash) and 34 and 48% was
excreted in the feces, respectively.5 After identical doses to bile duct cannulated rats, an
average of about 52 and 45% of an intravenous and subcutaneous dose was recovered in the
bile after 24 hours, indicating that biliary secretion was also an important route of
excretion.30
The profile of metabolites in biological matrices was similar with all dosage regimens.
Predominant urinary metabolites were the OH, COOH, G-OH, SO3OH and M-OH
compounds representing about 2 to 11 % of an intravenous or subcutaneous dose.5 The major
rat biliary metabolite was G-OH, which accounted for approximately 15% of the dose by
either route.30 Fecal metabolites consisted of OH, COOH, G-OH and SO3OH, each
comprising a mean of about 1.5 to 5.8% of the radioactive dose.5 Concentrations of
unchanged parent drug in bile and excreta samples were less than 1% of the dose.
The disposition, metabolism and excretion of [3H]dexmedetomidine were studied after single
subcutaneous and intravenous 20 µg/kg doses to rats.5 As part of a supporting role for
toxicology studies, the pharmacokinetics of dexmedetomidine have also been characterized
in rats following 20, 100 and 500 µg/kg subcutaneous doses of unlabeled drug.1 Rats or
tissues from rats have also been used in a number of specialized studies investigating tissue
distribution,14 in vitro metabolism,16,17 placental and lacteal transfer,15 and in vitro plasma
protein binding.9 The results of many of these studies are summarized in Tables 2, 6, 9, 10,
11, 12 and 13.
Single doses of dexmedetomidine were rapidly absorbed following 20,100 and 500 µg/kg
subcutaneous administration to rats, with peak plasma levels (Cmax) occurring within one
hour (Table 2).1 Cmax values increased with increasing doses and averaged 1.29, 10.65 and
71.59 ng/mL, respectively. Area under the curve (AUC) values averaged 3.4, 33.9 and 263.1
ng•h/mL in the same animals. Dose-normalized Cmax and AUC values (Cmax/D and AUC/D)
also increased with increasing dose, suggesting that dexmedetomidine pharmacokinetics
were non-linear in rats. This was accompanied by corresponding decreases in plasma
clearance (CLP), which averaged 5.0, 2.6 and 2.0 L/h•kg in the 20,100 or 500 µg/kg dose
groups, respectively. Dexmedetomidine plasma concentrations tended to be higher in
females in the 100 and 500 µg/kg groups. The terminal elimination half-lives for parent drug
were comparable in all treatment groups, averaging about 2.0 hours.
Based on the amount of tritiated water in the urine after 72 hours, it was estimated that less
than 1 % of the tritiated dose was converted to tritiated water in male and female rats after
intravenous or subcutaneous 20 µg/kg doses of [3H]dexmedetomidine.5 However, mean
levels of tritiated water in plasma slowly increased with time, averaging about 0.7 to 11% of
the total plasma radioactivity at 0.5 to 8 hours and 74 to 97% at 48 to 72 hours. Estimates of
plasma total radioactivity, parent drug and metabolites have been appropriately corrected.
Total radioactivity from subcutaneous 20 µg/kg doses of [3H]dexmedetomidine was rapidly

and well absorbed in rats of both sexes, but Cmax and exposure levels appeared to be slightly
greater in females (Table 9).5 Mean peak plasma levels of total radioactivity (2.12/2.83 ng
Eq/mL; M/F) were reached within 4 hours. However, significant levels of plasma
radioactivity were already present after 0.25 hours (2.1/2.2 ng Eq/mL; M/F) and remained
reasonably constant for up to 6 hours (1.5/2.7 ng Eq/mL; M/F; data not shown).5 Comparison
of the mean AUC0-72 for total plasma radioactivity (M+F) after intravenous (42.55 ng
Eq•h/mL) and subcutaneous (28.96 ng Eq•h/mL) doses indicated that absorption was high
and that there may have been kinetic differences for the two routes of administration.
As part of the same study, a separate group of rats received 20 µg/kg intravenous and
subcutaneous doses of [3H]dexmedetomidine for the purpose of determining plasma levels of
total radioactivity, parent drug and metabolites (Table 9).5 Blood samples from these rats
were obtained at 0.5,1, 2, 6 and 24 hours post-dose. Peak concentrations of unchanged parent
drug (2.28/1.78 ng/mL; M/F) after subcutaneous administration were observed at the first-
time point (0.5 hours) and were comparable between sexes. Under these conditions, mean
AUC values for dexmedetomidine (M+F) after intravenous (2.04 ng•h/mL) and
subcutaneous (4.53 ng•h/mL) doses appeared to be greater after subcutaneous
administration. The reason for this discrepancy is probably related to the lack of sufficient
blood sampling at the early time points, resulting in an underestimation of exposure to the
intravenous dose.
Tentatively identified circulating metabolites after administration of an intravenous or

subcutaneous 20 µg/kg dose of [3H]dexmedetomidine to rats consisted of the 3-hydroxy
metabolite (OH), the carboxylic acid metabolite (COOH), and the glucuronide (G-OH) and
sulfate (SO3OH) conjugates of the hydroxy metabolite (Table 9, Figure l).5 An apparent sex-
related difference in metabolism was observed since the levels of the SO3OH metabolite
were greater in females than in males, while those of the COOH component tended to be
higher in males than in females. Circulating levels of the glutathione (GS-OH) or
mercapturate (M-OH) conjugates of the OH metabolite were not observed. Several
additional plasma metabolites were detected in rats (M-2 to M-8) but these have not been
characterized. Mean exposure values (M+F) for the OH, COOH, G-OH and SO3OH
metabolites ranged from 0.62 to 3.63 ng• h/mL (2 to 11% of the AUC for total radioactivity)
after intravenous doses, and 0.46 to 2.28 ng• h/mL (1.5 to 7.5% of the AUC for total
radioactivity) after subcutaneous doses. Mean exposure to M-5 (3.78 and 2.97 ng•h/mL) and
M-6 (8.04 and 7.37 ng•h/mL) was also significant after both routes of administration.
In vitro studies using an ultrafiltration technique demonstrated [3H]dexmedetomidine was

highly bound to rat plasma proteins. At concentrations ranging from 0.85 to 85 ng base/mL,
the protein binding averaged 88.16% in rat plasma.9
The distribution of radioactivity was studied in tissues of male and female Sprague Dawley
rats and male Long Evans rats given a 20 µg/kg intravenous dose of [3H]dexmedetomidine.14
Drug-related radioactivity was rapidly and widely distributed throughout the animal body,
with highest mean concentrations in blood, plasma and selected tissues occurring from 0.25
to 12 hours post-dose (Table 10). The levels of radioactivity in the tissues exceeded those in
plasma on at least one collection point for all tissues except bone. Cmax values in plasma were
2.9 and 4.5 ng Eq/mL in males and females, respectively. Mean peak concentrations of
radioactivity were highest in the liver, adrenals, lungs, kidneys, small and large intestine
(including contents), stomach (including contents) and pancreas, with values ranging from
62.3 to 382.3 ng Eq base/g (Table 10). All other collected tissues contained less than 34 ng
Eq/g at all sampling times. The mean peak concentration of radioactivity in the brain was at
about five- to seven-fold greater than that in plasma.
Concentrations of radioactivity declined with time such that after 72 hours the levels in the
plasma and most tissues had decreased to about 0.1 to 5% of their respective peak values.
Elimination from the adrenals was slower and after 72 hours concentrations of radioactivity
(23.8 and 49.3 ng Eq base/g; M/F) were about 12 to 13% of their respective peak values and
222 to 1050 times greater than the corresponding plasma concentrations. Similar findings
were reported following a 40 µg/kg subcutaneous dose of the tritiated drug to rats.6
(241 ng Eq/g), kidneys (183 ng Eq/g) and eyes (without lens; 108 ng Eq/g) at 0.25 to 1 hour
after dosing (data not shown).14 Although the concentration of radioactivity in pigmented
(7.23 ng Eq/g) and non-pigmented (6.92 ng Eq/g) skin were comparable, the mean maximal
level in pigmented eyes was about 28-fold greater than that in non- pigmented eyes of male
Sprague Dawley rats (3.89 ng Eq/g), suggesting some binding of drug-related radioactivity
to melanin.
5.3.3.6 Placental and Lacteal Transfer
After a subcutaneous 15 µg/kg dose of [3H]dexmedetomidine to 18 day gravid rats,

radioactivity crossed the placental barrier and was distributed in maternal and fetal tissues.15
The highest mean concentrations of radioactivity in maternal and fetal tissues occurred at 1
hour post-dose for all tissues collected, except the maternal adrenal glands, amniotic fluid,
fetal blood and fetal kidneys which reached maximal levels at 8 hours.
The highest maternal levels (ng Eq/g base) were observed in the adrenals (275.73), lungs
(187.77), kidneys (62.08) and ovaries (26.47). The highest levels in the fetus were found in
blood (7.16), liver (5.13) and kidneys (4.78). The concentrations of radioactivity in blood,
plasma and maternal and fetal tissues declined over 72 hours to levels which were 0.15 to
38% of the mean peak values. Radioactivity was below the limit of detection in the maternal
brain, maternal heart, fetal heart and fetal kidneys at 72 hours post-dose.
Following administration of a subcutaneous 15 µg/kg dose of [3H]dexmedetomidine to

lactating rats, total radioactivity was distributed into the milk of dams and reached a
maximum mean concentration at 4 hours (1.57 ng Eq base/mL).15 Thereafter, levels of
radioactivity in milk decreased to non-detectable levels at 72 hours. The milk:plasma
concentration ratio was less than 1 at all collection time points (about 0.48 to 0.87) indicating
that radioactivity did not accumulate in the milk.
[3H]Dexmedetomidine is extensively metabolized in rats by Phase I (oxidative) and Phase II

(conjugative) pathways (Figure 1).5,6,16,17 In rats of both sexes, the primary metabolic route
involved the cytochrome P450-mediated hydroxylation of the methyl group at the 3-position
of the aromatic ring to form the hydroxy metabolite (OH). The OH metabolite can be
subsequently oxidized to produce the carboxy metabolite (COOH), or can undergo
conjugation by several pathways: 1) glucuronidation to form the G-OH metabolite; 2)
sulfation to produce the sulfate conjugate (SO3OH); and 3) conjugation with glutathione to
form the GS-OH metabolite, which undergoes secondary metabolism in the liver and is
excreted into the urine as the mercapturate conjugate (M-OH). A number of uncharacterized
metabolites were also detected in biological samples from rats. Concentrations of H-3, N-
Me, and G-Dex-1 and G-Dex-2 metabolites were below the limits of detection of the
analytical method and did not appear to be significant in vivo pathways in this species. The
levo-enantiomer as well as the N-methylated, OH and COOH metabolites are apparently
devoid of α2-receptor activity.16,22,29
In vitro studies in rats demonstrated that the OH metabolite of dexmedetomidine,

medetomidine and detomidine is formed by a microsomal high affinity, low capacity
monooxygenase system located almost exclusively in the liver.16 Lung, brain and kidney
microsomes were also able to hydroxylate these compounds, but the specific activity was no
more than 6% of that found with liver microsomes. It was also shown that these compounds
could undergo N-methylation primarily by rat kidney cytosol. N-Methyl transferase activity
in cytosol from liver, lungs and brain was less than 10% of the renal enzyme. It was
concluded that the kidney cytosolic N-methylase would be expected to contribute less to the
overall turnover of these substrates in vivo because of the lower capacity and affinity of the
enzymes for dexmedetomidine, as well as the relative size of the kidneys compared to the
liver.
5.3.3.8 Excretion
In rats, both urinary and fecal excretion are involved in eliminating dexmedetomidine and its
metabolites from the body (Table 6).5,30 After intravenous and subcutaneous administration
of a single 20 µg/kg dose of [3H]dexmedetomidine, an average of about 65 and 50% of the
dose was excreted into the urine (including cagewash) while 34 and 48% was recovered in
the feces after 3 days.5 Urinary excretion appeared to be greater in females whereas fecal
excretion tended to be higher in males. Biliary secretion also appears to be a major route of
elimination in rats of both sexes, since an average of about 52 and 45% of a 20 µg/kg
intravenous and subcutaneous dose of [3H]dexmedetomidine was found in the bile after 24
hours.30
Predominant metabolites in rat urine after intravenous and subcutaneous doses of

[3H]dexmedetomidine included OH, COOH, G-OH, SO3OH and M-OH metabolites (Table
11).5 Each of these metabolites accounted for an average (M+F) of approximately 2 to 9% of
the dose after both routes of administration. However, the levels of the SO3OH and M-OH
metabolites were about 9- to 100-fold higher in females. The uncharacterized M-2 and M-5
metabolites accounted for a mean of about 3 to 7% of the dose. Urinary concentrations of
unchanged parent drug were less than 1 % of the dose.
The major dexmedetomidine rat biliary metabolite was G-OH, representing an average
(M+F) of about 15% of a 20 µg/kg intravenous or subcutaneous dose (Table 13).30 Lesser
amounts of the COOH, SO3OH and the M-OH metabolite (0.26 to 2.64% of the dose) were
found but the free OH metabolite was not detected. The unidentified M-2 compound
represented about 7 to 9% of the dose in bile, whereas concentrations of M-5 were negligible
(0.3 to 0.5%). The finding of the GS-OH metabolite (predominantly in bile from female rats)
reinforces the notion that the M-OH metabolite in urine arises from reabsorption and further
metabolism of GS-OH in the liver or intestinal lumen.
The pattern of fecal metabolites was similar to that seen in bile and urine, except that M-OH
and GS-OH were not detected (Table 12).5 Predominant fecal metabolites were the OH,
COOH, G-OH and SO3OH, with mean recoveries ranging from 1.5 to 5.8% of an
intravenous or subcutaneous dose of the tritiated drug. The M-2 (about 1.2 to 1.4% of the
dose) and M-5 metabolites (5.7 to 7.7% of the dose) were also observed. The higher
concentrations of M-5 in feces than in bile suggests that M-5 may be formed by further
metabolism of a biliary metabolite by intestinal microflora. Unchanged parent drug was not
detected in feces.
5.3.4 Rabbits
The pharmacokinetics of dexmedetomidine were characterized in rabbits in support of

development and reproductive toxicity studies in the same species (Table 4).4 Four female
rabbits received a 96 µg/kg bolus intravenous dose of dexmedetomidine. The plasma
concentration time profiles were fit to a biexponential disposition model and characterized
by a mean apparent volume of distribution (VC) of 1.2 L/kg, a terminal phase distribution
volume (Vβ) of 6.0 L/kg and a terminal elimination half-life of 1.83 hours. The mean plasma
clearance (CLP) was 2.1 L/h•kg and the AUC0-∞ was 40.7 ng•h/mL.
5.3.5 Dogs
5.3.5.1 Summary
Single 50 and 250 µg/kg intramuscular doses of dexmedetomidine were rapidly absorbed by
male and female dogs, with peak plasma levels (Cmax) occurring in less than one hour.2
Greater than proportional increases in Cmax and AUC values as the dose was increased
indicated non-linear pharmacokinetics. The AUC ratio for parent drug after intravenous 50
µg/kg doses to dogs was 0.6. The intravenous plasma concentration time profile of
dexmedetomidine was fit to a two compartment open model with a volume of distribution
estimate of 0.41 L/kg and 0.93 L/kg for VC and Vβ, respectively. Plasma clearance values
averaged 0.9 L/h•kg. The mean plasma elimination half-life after intravenous administration
was 0.68 hours; that after intramuscular doses ranged from 0.85 to 1.31 hours. In a multiple
dose study, dogs received intrathecal doses of dexmedetomidine (0.2, 1.2 and 8 µg/kg/day)
for 22 consecutive days.3 The plasma AUC values for parent drug on Day 1 (0.007, 0.124
and 1,80 ng• h/mL) were directly comparable on Day 22, indicating that the drug did not
accumulate under these conditions.
Total radioactivity from a 20 µg/kg subcutaneous dose of [3H]dexmedetomidine was well

absorbed by dogs.7 Comparison of the AUC0-72 for total plasma radioactivity after a
subcutaneous dose (110.4 ng•h/mL) with that after intravenous administration (101.8
ng•h/mL) indicated excellent absorption of the radioactive dose. The average Cmax for
subcutaneously administered dexmedetomidine (4.39 ng /mL) occurred at 2 to 4 hours post-
dose. Comparison of mean parent drug exposure after subcutaneous (15.14 ng• h/mL) and
intravenous (19.03 ng•h/mL) suggested that the subcutaneous dose was bioequivalent.
Plasma metabolites included the OH, COOH, G-OH and SO3OH metabolites which
individually accounted for about 1 to 8% of the AUC for total plasma radioactivity. About
65% of the total plasma radioactivity has not been characterized.
The levo-enantiomer as well as the N-methylated and OH, G-OH and COOH metabolites are
apparently devoid of α2-receptor activity. 16,22,29 The plasma protein binding of
[3H]dexmedetomidine averaged about 93% in dog plasma.9
Dexmedetomidine was extensively metabolized in dogs.7,18 In vivo studies suggest that a

major identified pathway involves direct hydroxylation of dexmedetomidine to form the OH
metabolite, with secondary metabolism of the OH component to form the COOH metabolite
as well as the glucuronide (G-OH) and sulfate (SO3OH) conjugates.7 In vitro studies with
dog liver slices have also shown that N-methylation is also predominant in the dog.18
After intravenous or subcutaneous administration of a 20 µg/kg dose of

[3H]dexmedetomidine to dogs, 82 to 83% of the dose was excreted into the urine (including
cagewash) and about 13% was excreted in the feces after 3 days.7 Major urinary metabolites
include COOH, G-OH and SO3-OH, which account for an average of about 8 to 15% of the
dose. About 50% of the urinary radioactivity has not been characterized. Notable fecal
metabolites consist of the OH, COOH and SO3OH compounds, representing about 0.2 to 2%
of the dose.
The disposition and metabolism of [3H]dexmedetomidine have been investigated in dogs

after subcutaneous and intravenous administration of a 20 µg/kg dose.7 In vitro metabolism
experiments have also been conducted using precision-cut dog liver slices.18 The
pharmacokinetics of the drug have been characterized in dogs following a single 50 µg/kg
intravenous dose as well as 50 and 250 µg/kg intramuscular doses.2 Dogs have also been
used in pharmacokinetic studies after single and multiple (22 days) 0.2, 1.2 and 8.0 µg/kg
intrathecal doses of dexmedetomidine.3 The results of some of these studies are summarized
in Tables 3, 5, 6, 7, 8, 14, 15 and 16.
Single 50 and 250 µg/kg intramuscular doses of dexmedetomidine were rapidly absorbed by
male and female dogs, with peak plasma levels (Cmax) being found in less than one hour
(Table 3).2 Greater than proportional increases in Cmax and AUC values were noted as the
dose was increased, indicating that dexmedetomidine pharmacokinetics were nonlinear in
dogs. Cmax values averaged 12.04 and 160.5 ng/mL after 50 and 250 µg/kg intramuscular
doses, respectively; corresponding AUC values were 25.66 and 428.4 ng•h/mL. The AUC
ratio after a single intramuscular and intravenous 50 µg/kg dose to dogs was about 0.6. The
intravenous plasma concentration time profile of dexmedetomidine was fit to a two
compartment open model with a volume of distribution estimate of 0.41 L/kg and 0.93 L/kg
for VC and Vβ, respectively. Plasma clearance values were similar in males and females,
averaging 0.9 L/h•kg. The mean plasma elimination half-life of dexmedetomidine after
intravenous administration was 0.68 hours. The half-life after intramuscular doses ranged
from 0.85 to 1.31 hours and showed a tendency to be longer with higher doses.
Intrathecal doses of dexmedetomidine (0.2, 1.2 and 8.0 µg/kg/day) were also administered to
dogs for 22 consecutive days.3 Mean AUC values averaged 0.007, 0.124 and 1.80 ng•h/mL
on the first day of dosing (Table 3). These values did not change with multiple dosing for 22
days, averaging 0.009, 0.122 and 1.86 ng•h/mL for the same dose groups, suggesting that
accumulation of the drug did not occur during this time.
Based on the amount of tritiated water excreted into the urine after 72 hours, it was estimated
that less than 0.9% of the tritiated dose was converted to tritiated water in male and female
dogs after intravenous or subcutaneous 20 µg/kg doses of [3H]dexmedetomidine.7 However,
mean levels of tritiated water in plasma slowly increased with time, averaging about 2% of
the total plasma radioactivity up to 6 hours and 74 % at 120 hours. Estimates of plasma total
radioactivity, parent drug and metabolites have been appropriately corrected.
Mean peak levels of total radioactivity (9.27 ng Eq/mL) after a 20 µg/kg subcutaneous dose
of [3H]dexmedetomidine to male and female dogs occurred within 6 hours (Table 14).7
Comparison of the AUC0-120 for total plasma radioactivity after intravenous (101.81 ng
Eq•h/mL) and subcutaneous (110.38 ng Eq•h/mL) doses indicated quantitative absorption of
the [3H]dexmedetomidine subcutaneous dose. Mean peak concentrations of
dexmedetomidine (4.39 ng/mL) were observed at 2 to 4 hours and declined with time.
Unchanged parent drug could not be detected in the plasma after 12 hours. Comparison of
the AUC0-12 for dexmedetomidine following intravenous (15.14 ng•h/mL) and subcutaneous
(19.03 ng•h/mL) administration indicated excellent bioavailability. Exposure to parent drug
after both routes of administration represented about 15 to 17% of the AUC0-120 for total
plasma radioactivity. Expressed as mean AUC0-12 values, major identified plasma
metabolites included the OH (about 1 ng•h/mL), COOH (4.58 to 5.0 ng•h/mL), G-OH (5.94
to 8.37 ng•h/mL) and SO3OH (7.2 to 7.67 ng•h/mL). A number of unidentified plasma
metabolites (D-2, D-4, D-6 and D-7) were also detected, affording average AUC0-12 values of
about 1.2 to 6.8 ng•h/mL (1.2 to 6.7% of the AUC120 for total plasma radioactivity). The GS-
OH, M-OH, G-Dex 1, G-Dex-2, N-Me or related N-Me metabolites were not detected. Other
uncharacterized metabolites accounted for about 65% of the AUC0-120 for total plasma
radioactivity.
In vitro studies using an ultrafiltration technique demonstrated that binding of

[3H]dexmedetomidine to dog plasma proteins averaged about 92.58% at drug concentrations
ranging from 0.85 to 85 ng base/mL.9
[3H]Dexmedetomidine was extensively metabolized in the dog (Figure 1).7,17 In male and
female dogs, dexmedetomidine was metabolized by an apparently cytochrome P450-
dependent hydroxylation of the methyl group at the 3-position of the aromatic ring to form
the hydroxy metabolite (OH) as well as hydroxylation at the methyl position on the
methylene bridge to form the H-3 metabolite. The OH metabolite was then oxidized to
produce the carboxy metabolite (COOH), or conjugated by two pathways: 1) glucuronidation
to form the G-OH metabolite and 2) sulfation to produce the SO3OH conjugate. The GS-OH
or M-OH conjugates of the OH metabolite have not been detected Although metabolites
pertaining to N-methylation of parent drug have not been found in vivo, experiments with
dog liver slices demonstrated that this pathway was significant in vitro.18 In the latter studies,
N-methyl dexmedetomidine (N-Me) and related metabolites (N-Me-OH, N-Me-COOH, N-
Me-G-OH and N-Me- SO3OH) accounted for an average of about 50% of the metabolites
formed after incubation of [3H]dexmedetomidine with dog liver slices. Tentative
identification of these metabolites was made based on comparable HPLC retention times of
authentic reference standards, hydrolysis of conjugates and analysis of several isolated
metabolites by LC/MS. The reason for the divergent findings between in vivo and in vitro
experiments is not known, but it seems possible that the N-Me metabolite formed by dogs in
vivo may undergo subsequent metabolism by 1) a CYP-mediated N-demethylation to
regenerate dexmedetomidine, or 2) oxidation/conjugation of the intact N-Me compound by a
pathway similar to that of dexmedetomidine. A number of other uncharacterized metabolites
were also detected in dog urine which may represent products of hydroxylation on other
portions of the molecule followed by conjugation reactions in a manner comparable to that
proposed for parent drug. Direct glucuronidation of dexmedetomidine to form the two N-
glucuronides (G-Dex-1 and G-Dex-2) did not appear to be a significant pathway in dogs. The
levo-enantiomer as well as the N-methylated and OH, G-OH and COOH metabolites are
apparently devoid of α2-receptor activity.16,22,29
5.3.5.6 Excretion
After intravenous and subcutaneous administration of a 20 µg/kg dose of

[3H]dexmedetomidine to male and female beagle dogs, an average of about 82 to 83% of the
radiolabel was excreted in the urine (including cagewash) and approximately 13% was
recovered in the feces after 3 days (Table 6).7
The pattern of urinary metabolites following a 20 µg/kg intravenous or subcutaneous dose of

[3H]dexmedetomidine to dogs was generally similar to that found in plasma. No remarkable
sex-related differences in metabolism were evident. Expressed as a mean percent of the dose
for males and females, tentatively identified metabolites included the OH (1.3 to 2.2%);
COOH (11.8 to 13.2%), G-OH (8.1 to 10.8%) and SO3OH (13.1 to 15.3%) (Table 15).7
Collectively, these metabolites accounted for about 47% of the total urinary radioactivity.
Unidentified metabolites were arbitrarily designated as D-1 to D-6 and represented an
average of about 0 to 10% of the dose, representing about 40% of the total urinary
radioactivity. Approximately 13% of the urinary radioactivity could not be assigned to
identified metabolites. Detectable levels of GS-OH, M-OH, G-Dex-1, G-Dex-2, N-Me and
related N-Me metabolites were not found. Free parent drug represented less than 1% of the
dose.
Notable biotransformation products found in dog feces were the OH, COOH, SO3OH, D-3
and D-5 metabolites, which accounted for about an average of about 0.2 to 2.9% of the dose
(Table 16).7 Unchanged parent drug, and the G-OH, GS-OH, M-OH, N-Me, G-Dex-1 and G-
Dex-2 metabolites were not observed. About 70% of the fecal metabolites are unknown.
5.3.6 Humans
5.3.6.1 Summary
The highest mean levels of total plasma radioactivity (3.18 ng Eq/g) and dexmedetomidine
(3.11 ng/g) were found 10 minutes after the end of the intravenous infusion of a 2 µg/kg dose
of [3H]dexmedetomidine to normal human subjects.8 Comparisons between parent drug and
metabolites for all 5 subjects in the study were made over the 24 hour time period. On this
basis, unchanged parent drug represented a mean of about 15% of the AUC for total plasma
radioactivity over 24 hours.
Major plasma metabolites were G-Dex-1 (7.80 ng Eq•h/g) and G-Dex-2 (1.37 ng Eq•h/g)
which collectively accounted for about 41% of the AUC0-24 for total plasma radioactivity.8
Other significant metabolites were H-3 and G-N-Me-OH with AUC0-24 values of 3.48 and
4.56 ng Eq•h/g, respectively (about 16 and 20% of the AUC0-24 for total plasma
radioactivity). Minor plasma metabolites were COOH, H-2, N-Me and N-Me-COOH with
AUC0-24 values ranging from 0.07 to 0.67 ng Eq•h/g.
In vitro, it appears that G-Dex-1 and G-Dex-2 exhibit characteristics of weak pre-synaptic
agonists in both the rat vas deferens and guinea pig ileum assays, being 1 to 2 orders of
magnitude less potent than parent drug.28 However, no central or peripheral α2-agonist
activity was found in vivo (mydriasis model), ostensibly because the glucuronides, which are
resistant to hydrolysis, could not penetrate the central nervous system and therefore would
not be expected to contribute any pharmacological activity. The levo-enandomet as well as
the N-methylated and OH, G-OH and COOH metabolites are apparently devoid of α2-
receptor activity.16,22,29
[3H]Dexmedetomidine is extensively metabolized in humans (Figure 1).8,19,20 Two

predominant non-CYP-mediated metabolic pathways are direct N-glucuronidation to form
G-Dex-1 and G-Dex-2, and N-methylation to produce the N-methyl metabolite (N-Me). The
intact N-Me metabolite can be subjected to further metabolism in a manner similar to
dexmedetomidine; i.e. hydroxylation to form the N-Me-OH metabolite, oxidation of NMe-
OH to form the carboxylic acid derivative (N-Me-COOH), or conjugation to produce the
corresponding O-glucuronide (G-N-Me-OH). The possible N-demethylation of the N-Me
metabolite to regenerate dexmedetomidine could not be evaluated. Other metabolic pathways
for dexmedetomidine in humans also include a largely CYP2A6- mediated hydroxylation to
form the hydroxy (OH) and H-3 derivatives,21 as well as subsequent biotransformation of the
OH metabolite to produce the COOH and G-OH metabolites.8
After intravenous infusion of a 2 µg/kg dose of [3H]dexmedetomidine, approximately 89 to

95% of the dose was excreted in the urine while 4 to 6% was recovered in the feces after 9 to
10 days (Table 6).8,31 Major urinary metabolites were the G-Dex-1 and G-Dex-2 N-
glucuronides, collectively accounting for about 34% of the dose (Table 7).8 Other
metabolites, expressed as a percent of the dose, were G-N-Me-OH (14.5%), G-OH (7.7%),
COOH (4.8%), N-Me-COOH (3.8%) and OH (1.1%). Fecal metabolites included OH,
COOH, G-OH, G-Dex-1, G-Dex-2, G-N-Me-OH and H-3 individually accounting for 0.01 to
0.47% of the dose. Unchanged parent drug was less than 1% of the dose in excreta.
Two studies have been conducted to determine the disposition and metabolism of
[3H]dexmedetomidine in normal male human subjects after intravenous infusion of a 2 µg/kg
dose of the radiolabeled drug.8,31 In the first study sponsored by Orion- Farmos, excellent
recovery data were obtained, but identification of dexmedetomidine metabolites was
inconclusive,19 and plasma tritiated water was not measured.31 Consequently, a second
human study was sponsored by Abbott Laboratories to define the dexmedetomidine
metabolic pathway in human subjects; all metabolism data reported here were derived from
this study.8 The conversion of the dextro to the levo-enantioxner in vivo has also been
addressed.23 In vitro metabolism studies were also conducted using human liver microsomes
and human B-lymphoblastoid microsomes containing cDNA-expressed CYP proteins, as
well as human liver slices.20,21 The in vitro human plasma protein binding of radiolabeled
dexmedetomidine, protein binding interactions as well as red blood cell distribution have
also been examined.9-12 The results of some of these studies are summarized in Tables
6,7,8,17,18 and 19.
5.3.6.3 Dexmedetomidine and Plasma Metabolites
Following a 2 µg/kg intravenous infusion of [3H]dexmedetomidine to human subjects, mean

plasma levels of tritiated water represented less that 1% of the total plasma radioactivity up
to 8 hours post-dose and gradually increased with time before reaching a plateau after 6
days.8 At this time mean levels of tritiated water averaged about 43% of the total plasma
radioactivity and remained fairly constant up to 9 days. Corrections were made if tritiated
water exceeded 1 % of the total plasma radioactivity. Based on the amount of tritiated water
in the urine after nine days, it was estimated that less than 1% of the dose was converted to
tritiated water.
The pattern of radioactivity was remarkably similar in all subjects. The concentration of total
radioactivity decreased from a maximum value of 3.18 ng Eq/g at 10 minutes to 1.51 ng
Eq/g at 30 minutes.8 After 30 minutes, the levels rose again to reach a mean maximum value
of 2.02 ng Eq/mL at 2 hours, primarily due to the appearance of parent drug glucuronides
(G-Dex-1 and G-Dex-2). Thereafter, levels of radioactivity declined gradually over a period
of 9 days and traces of radioactivity were still present up to 24 days. Including a 23/24 day
time point, the mean elimination half-life for total plasma radioactivity was estimated to be
10.75 days, which is comparable to that of tritiated water in man (9.46 days). Since the
concentrations of radioactivity in the 23/24 day plasma samples were very low, the
contribution of tritiated water could not be determined. Consequently, the possible presence
of small concentrations of a long-lived metabolite(s), as previously suggested,31 cannot be
ruled out completely.
The highest mean concentrations of [3H]dexmedetomidine after a 2 µg/kg intravenous

infusion in human subjects were reached 10 minutes after the end of the infusion period
(3.11 ng/g) and declined biexponentially to 0.01 ng/g at 12 hours.8 Due to the relative
insensitivity of the radiometric analytical assay at later time points, parent drug could not be
reliably detected in plasma up to 24 hours. Consequendy, pharmacokinetic data could be
obtained for only 3 of the 5 subjects who participated in the study. For these individuals, the
harmonic mean terminal elimination half-life of dexmedetomidine was estimated to be about
2.85 hours, the mean extrapolated AUC0-∞, was 3.49 ng•h/mL, the total plasma clearance
was 42.6 L/h and the distribution volume at steady-state (Vss) was 143.9 L.8 Since the
extrapolated AUC0-∞ for dexmedetomidine in these three subjects was only slightly greater
(7%) than the mean AUC0-24 values (3.26 ng•h/g) for all 5 subjects, comparisons between
parent drug and metabolites for all subjects were made based on AUC0-24 values. On this
basis, comparison of the mean AUC0-24 for total plasma radioactivity (22.17 ng•h/g) with that
of dexmedetomidine over the same time period (3.26 ng•h/g) indicated that unchanged
parent drug accounted for an average of about 15% of the total AUC0-24 for plasma
radioactivity.
Major plasma metabolites were G-Dex-1 (7.80 ng Eq•h/g) and G-Dex-2 (1.37 ng Eq•h/g)
which collectively accounted for about 41% of the AUC0-24 for total plasma radioactivity
(Table 17).8 Other significant metabolites were H-3 and G-N-Me-OH with AUC0-24 values of
3.48 and 4.56 ng Eq•h/g, respectively (about 16 and 20% of the AUC0-24 for total plasma
radioactivity). Since the biotransformation of [3H]dexmedetomidine to H-3 occurs at the site
of the tritium label (bridge methyl group), the subsequent partial loss of tritium probably
accounts for the formation of tritiated water found in plasma. The elimination half-life of H-
3 in one of the subjects was estimated to be about 14 hours.8 Minor plasma metabolites were
COOH, H-2, N-Me and N-Me-COOH with AUC0-24 values ranging from 0.07 to 0.67 ng
Eq•h/g. The OH, SO3OH, GS-OH, M-OH and N-Me-OH metabolites were not detected in
human plasma. Approximately 3% of the AUC for total radioactivity has not been
characterized (Table 5).
The possible in vivo conversion of dexmedetomidine to the inactive enantiomer,

levomedetomidine, was also addressed using selected human plasma and urine samples from
each subject.8’23 Utilizing a radiometric chiral chromatography method with a lower limit of
detection of 0.02 ng/mL, unchanged [3H]levomedetomidine was not detected in any of the
plasma samples analyzed. Slight amounts of levomedetomidine N-glucuronide (G-levo)
were detected in plasma (< 0.5% of the AUC for total plasma radioactivity) and urine (<
1.5% of the dose), but the extent of possible chiral inversion could not be evaluated since
traces of [3H]levomedetomidine were present as an impurity in the original
[3H]dexmedetomidine dose solution. The levomedetomidine "impurity" contributed to the
already low levels of G-levo detected, and indicated that the chiral inversion pathway was of
minimal significance in humans and of doubtful clinical relevance.
The in vitro protein binding of [3H] dexmedetomidine in human plasma was determined with
an ultrafiltration technique.9 At drug concentrations ranging from 0.85 to 85 ng/mL, protein
binding averaged 93.72%. [3H]Dexmedetomidine was bound to physiological concentrations
of human serum albumin (HSA) and α1-acid glycoprotein (α1-AGP), but the binding to
albumin was about 1.3-fold greater.10 The binding of [3H]dexmedetomidine to HSA (40
mg/mL) averaged 80.75% and was concentration- independent from 0.85 to 85 ng base/mL.
The binding of the tritiated drug to α1-AGP (0.8 mg/mL) averaged 63.96% over the same
drug concentration range. Since the binding of the drug to either matrix was lower than
plasma, other plasma proteins may also be involved.
In vitro protein binding interaction studies in human plasma between [3H]dexmedetomidine

(0.6 ng base/mL) and fentanyl, ketorolac, theophylline, digoxin, and lidocaine were
conducted.11 The [3H]dexmedetomidine plasma protein binding was only slightly decreased
(less than 1%) by the addition of any of these compounds. Moreover, the human plasma
protein binding of radiolabeled phenytoin, warfarin, ibuprofen, propranolol, theophylline and
digoxin was not appreciably changed in the presence of dexmedetomidine (0.6 ng
base/mL).12
In vitro studies with [3H]dexmedetomidine at concentrations of 0.5 and 5.0 ng base/mL

showed that the binding of dexmedetomidine to human red blood cells is low.13 Over the
concentration range studied, the fraction of drug bound to red cells (frbc) averaged 0,183, the
red blood cell to plasma concentration ratio (Crbc/Cp) averaged 0.325 and the whole blood to
plasma concentration ratio (Cblood/Cp) averaged 0.723 for both sexes.
Results from in vivo and in vitro metabolism studies indicated that [3H]dexmedetomidine
was extensively metabolized in humans (Figure 1).8,19,20 Two predominant non-CYP
mediated metabolic pathways appeared to involve direct N-glucuronidation and N-
methylation.8 Dexmedetomidine can undergo glucuronidation on either nitrogen in the
imidazole ring to form two N-glucuronides, G-Dex-1 and G-Dex-2. Alternatively, the drug
can be methylated with the resultant formation of an N-methyl derivative (N-Me). The intact
N-Me metabolite can presumably be subjected to further metabolism in a manner similar to
dexmedetomidine; i.e. CYP-mediated hydroxylation to form the N-Me- OH metabolite,
oxidation of N-Me-OH to form the carboxylic acid derivative (N-Me- COOH), or
conjugation to produce the corresponding O-glucuronide (G-N-Me-OH).
The possible N-demethylation of the N-Me metabolite to regenerate dexmedetomidine could
not be evaluated. The N-Me metabolite as such, has not been detected in biological samples
from humans, but its formation has been inferred by the tentative identification of related
metabolites. Other metabolic pathways for dexmedetomidine in humans also include a
largely CYP2A6-mediated hydroxylation to form the hydroxy (OH) and H-3 derivatives,21 as
well as subsequent biotransformation of the OH metabolite to produce the COOH and G-OH
metabolites.8 Further metabolites of the H-3 metabolite have not been observed in vivo.
In vitro, it appeared that G-Dex-1 and G-Dex-2 exhibited characteristics of weak pre-
synaptic agonists in both the rat vas deferens and guinea pig ileum assays, being 1 to 2
orders of magnitude less potent than parent drug.28 However, no central or peripheral α2-
agonist activity was found in vivo (mydriasis model), ostensibly because the glucuronides,
which are resistant to hydrolysis, could not penetrate the central nervous system and
therefore would not be expected to contribute to any pharmacological activity. The levo-
enantiomer as well as the N-methylated and OH, G-OH and COOH metabolites are
apparendy devoid of α2-receptor activity. 16,22,29
5.3.6.7 CYP-Mediated Metabolism
The NADPH-dependent oxidative metabolism of [3H]dexmedetomidine was also examined

using suitably fortified human liver microsomes and human B-lymphoblastoid microsomes
containing cDNA-expressed cytochrome P450s (CYP).21 Two oxidative metabolites were
detected: 1) the 3-hydroxy metabolite (OH) and 2) a metabolite tentatively identified as that
formed by hydroxylation at the methyl position on the methylene bridge (H-3; Figure 1).
Both metabolites have been found in plasma samples from a previous study with
[3H]dexmedetomidine in humans.8 Data from human microsomes, purified CYP enzymes
and CYP-selective inhibitors suggested that the formation of OH and H-3 was mediated
largely by CYP2A6, although other CYP forms (CYP1A2, CYP2E1, CYP2D6 and
CYP2C19) may also be involved. These findings are consistent with those which
demonstrated dexmedetomidine to be a broad-spectrum inhibitor of the metabolism of a
number of CYP-selective substrates.24-27 However, since the in vitro IC50 or Ki values for
dexmedetomidine inhibition (0.2 to 70 µM) were much greater than the targeted steady-state
plasma concentrations in humans (about 1.25 ng/mL; 6 nM), clinically relevant drug
interactions between dexmedetomidine and these CYP isoforms are not anticipated.
5.3.6.8 Excretion
After intravenous infusion of a 2 µg/kg dose of [3H]dexmedetomidine, human subjects

excreted an average of about 92% of the dose into the urine within 9 to 10 days (Table 6).8,31
Approximately 5% of the dose was recovered in the feces. Total recovery of radioactivity
was excellent, averaging 97%.
Unchanged parent drug was not detected in the urine, suggesting extensive metabolism in
humans.8.19 Major urinary metabolites were G-Dex-1, G-Dex-2 and G-N-Me-OH, accounting
for 19.56, 14.43 and 14.51% of the dose, respectively (Table 18).8 Other metabolites,
expressed as a percent of the dose, were G-OH (7.66%), COOH (4.80%), N-Me-COOH
(3.76%) and OH (1.11%). The SO3OH, M-OH, GS-OH, N-Me, H-2 and H-3 metabolites
were not found. Based on this distribution of metabolites, N- glucuronidation (G-Dex-1 + G-
Dex-2) accounted for 34% of the dose, the N-methylation pathway (N-Me, G-N-Me-OH, and
N-Me-COOH) for about 18% and the hydroxylation pathway (OH, COOH and G-OH) for
approximately 14% of the dose in urine. Collectively, these pathways represented about 66%
of the dose in urine and 70% of the total radioactivity; approximately 30% of the urinary
radioactivity has not been characterized.
Tentatively identified metabolites in human feces consisted of the OH, COOH, G-OH, G-
Dex-1, G-Dex-2, G-N-Me-OH, H-3 and N-Me-COOH metabolites, each accounting for less
than 0.5% of the radioactive dose (Table 19).8 Unchanged parent drug in human feces
represented 0.06% of the dose. About 68% of the fecal radioactivity has not been
characterized.
5.3.7 Human and Interspecies Comparison
In rats, dogs and humans, intravenous and/or subcutaneous doses of [3H]dexmedetomidine

are eliminated by extensive metabolism and excreted largely into the urine. In humans and
dogs about 80 to 90% of the dose is found in the urine, while 5 to 13% is recovered in the
feces. Urinary excretion is somewhat less in rats (50 to 65%), with 34 to 48% of the dose
being excreted in the feces, primarily via the bile. Plasma protein binding was generally
comparable among species, averaging 88.16% in rats, 92.58% in dogs and 93.72% in
humans.
Under the experimental conditions described, dexmedetomidine metabolic pathways were

found to be species-dependent. Similarities in the pattern of identified plasma and urinary
metabolites were found in rats and dogs, but the pattern was unlike those found in humans,
suggesting that neither species represents an ideal model for the known metabolism of
dexmedetomidine in man. Metabolites common to each species have been detected or
inferred, but a major metabolic difference was the relative inability of rats and dogs to form
the G-Dex-1 and G-Dex-2 glucuronides. For example, the major metabolic pathway in rats
was an apparently CYP-driven hydroxylation (oxidation) to form the OH metabolite. All
other metabolites found represented further biotransformation products of the OH metabolite
(COOH, G-OH, SO3OH, GS-OH and M-OH). Collectively, exposure to this group of
metabolites in rats accounted for an average of about 37% of the AUC for plasma
radioactivity, 56% of the total urinary radioactivity and 45% of the radioactivity in bile. The
M-OH metabolite was found only in rat urine and not the urine from dogs or humans. No
evidence of a significant direct N-glucuronidation or N-methylation pathway was obtained
from in vivo or in vitro studies in rats. Rat kidney cytosol was shown to N-demethylate
dexmedetomidine in vitro, but the system was of low affinity and low capacity and believed
not to be quantitatively important in the metabolism of the drug. This may explain the lack of
N-Me or related metabolites in rats and rat liver slices. The H-3 metabolite, which is formed
by hydroxylation of [3H]dexmedetomidine on the bridge methyl group, was not found in
biological samples from rats. Since the tritium label is located on the bridge methyl group,
formation of H-3 results in the partial loss of the tritium label with the subsequent formation
of tritiated water. The presence of tritiated water in rat plasma samples implies that H-3 was
also formed in this species, but may have been further metabolized and excreted as an
unidentified metabolite. It was estimated that less than 1 % of the dose was convened to
tritiated water in rats, dogs and humans. If it was assumed that all of the tritiated water is a
product of H-3 formation, this pathway was not a major contributor to the total metabolism
of dexmedetomidine in all species studied.
Relative Dexmedetomidine Pathways

Pathway Rat Dog Human
OH ++++ ++++ ++
GS-OH + ± ±
N-Me ± +++* ++
G-Dex-1/2 ± ± ++++
* = in vitro dog liver slices
Except for the lack of the GS-OH and M-OH metabolites, results from in vivo studies have
shown the hydroxylation pathway (OH) is ostensibly the predominant metabolic route in
dogs. In dogs, the OH, COOH, G-OH and SO3OH metabolites represented 17 to 49% of the
total radioactivity in plasma and urine. Although detectable levels of the N-Me metabolite or
known related metabolites were not found in vivo, in vitro studies have shown that about
50% of the metabolites formed after incubation of tritiated dexmedetomidine with dog liver
slices represent the N-Me or related compounds. A plausible explanation may be that the N-
Me metabolite formed in vivo was N- demethylated to regenerate parent drug which was
then metabolized to the OH, COOH, G-OH and SO3OH metabolites. As noted previously in
rats, formation of the H-3 metabolite in dogs was inferred from the presence of tritiated
water in plasma samples. Direct N-glucuronidation of parent drug does not appear to be a
dominant pathway in dogs.
Prominent metabolic pathways in humans were N-glucuronidation (G-Dex-1 and G-Dex-2)

and N-methylation (N-Me, N-Me-COOH, G-N-Me-OH) which accounted for about 41 and
21% of the plasma radioactivity and 36 and 19.5% of the total urinary activity, respectively.
The 3-hydroxylation pathway (OH, COOH, G-OH) was somewhat less in humans,
accounting for about 15% of the plasma and urinary radioactivity. The H-3 metabolite was
detected only in human plasma and accounted for about 16% of the AUC for total plasma
radioactivity. The absence of detectable levels of H-3 in human urine supports the concept
that it may have been subjected to further metabolism and excreted into the urine as an
unidentified metabolite. The dose of [3H]dexmedetomidine in the human study (2 µg/kg) was
10-fold lower than that used in the animal studies (20 µg/kg). It is possible that the pattern of
metabolites in humans at much higher doses may shift due to saturation of one or more lower
capacity pathways; saturation of the high capacity glucuronidation pathway, however, seems
unlikely.
A considerable number of metabolites in the urine from all species have not been
characterized. These components may arise from different routes of metabolism, including
hydroxylation of parent drug of the N-Me metabolite on other portions of the molecule
(aromatic) followed by conjugation, or possibly by other non-CYP mediated reactions.
5.3.8 Chemistry
5.3.8.1 Synthesis of Radiolabeled Medetomidine
Radiolabeled medetomidine was prepared at high specific activity by Amersham

Corporation from [3H]methyl iodide and the bridge ketone based on a published method
{Kudzma, L. and Turnbull, S., Synthesis, 1021 (1991)}:
Mg
CT3I CT3MgI
1) CT3MgI
2) H3O+
1) Li/NH3/NH4Cl
2) HCl
HCl
5.3.8.2 Preparative Separation Dexmedetomidine
The aim of this work was to prepare microgram quantities of the tritiated dextro and levo-
enantiomers of medetomidine of high optical purity. A published method exists for the
separation of the two enantiomers using a commercially available α1-acid glycoprotein (α1-
AGP) column operated in a reversed-phase mode with a phosphate buffer as the mobile
phase. However, the poor capacity factor of this column and the use of phosphate salt in the
method prohibited its use for preparative resolution of the enantiomers. Therefore, a direct,
fast and reproducible separation method using a commercially available chiral stationary
phase (CSP) composed of cellulose tris (3,5-dimethylpheriyl- carbamate) chemically bonded
to 3-aminopropyl silica gel, Chiralcel OD, and a mobile phase consisting of n-hexane, 2-
propanol and trifluoroacetic acid was developed and used.
About 4.78 mCi of dextro enantiomer (D-enantiomer) and 4.92 mCi of levo-enantiomer (L-
enantiomer) were obtained. They were shown to have a specific activity of 76.0 Ci/mmol
and 84.1 Ci/mmol, respectively, with radiochemical purities of >96% and optical purities of
>98%. The dextro enantiomer was assigned Lot No. 50498-ST-113 and the levo-enantiomer
was assigned Lot No. 50498-ST- 111.32
5.3.8.3 Assays for Dexmedetomidine
An analytical method for the quantitation of dexmedetomidine (Abbott-85499) in human

plasma was developed using gas chromatography with mass spectrometric detection (GC-
MS).33 Compound d-MPV-872 AII was used as the internal standard. The assay procedure
consisted of extractive derivatization of both analytes from a plasma matrix using
pentafluorobenzoyl chloride (PFB-CI) as the derivatization reagent and hexane as the
extraction solvent. Resolution of the analyte peaks was achieved using a DB-1701 (J & W,
30 m x 0.25 mm x 0.25 µ) capillary column with a carrier gas of helium. Analytes were
monitored using mass spectrometry (HP MS Engine®) with negative chemical ionization
(NCI). The chromatographic run time was about 9.3 minutes.
The standard curves derived from the peak area ratio (analyte/internal standard) versus
concentration of Abbott-85499 in human plasma were linear over the range of approximately
10 to 1500 pg/mL, with correlation coefficients ranging from 0.992 to 0.998. The Y-
intercepts were not significantly different from zero. The lowest standard level at 10 pg/mL
had an inter-day accuracy of 97.7% with a CV of 9.5% for nine measurements, indicating
that this concentration could be used as the lower limit of quantitation (LOQ).
The intra-assay accuracy for Abbott-85499 in human plasma was excellent. The mean of
three replicates for the four QC levels derived from the three day validation ranged from
102.1 to 116.7% of the theoretical concentration, with CVs ranging from 0.7 to 16.6%. The
inter-assay accuracy and precision were also good. Mean assay results for the three different
days of analysis were 114.7, 110.8, 111.8 and 105.9% of the theoretical concentrations for
the four QC levels of 10.5, 52.5, 839.1 and 1573.4 pg/mL, respectively. The corresponding
inter-assay CVs were 3.2, 6.8, 6.3 and 8.5%. The method was also validated in dog plasma.
Similar performance was obtained in this matrix. There were no anomalies affecting
precision or accuracy that could be assigned to the matrix. Intra-assay mean accuracy for
triplicate QCs in dog plasma ranged from 87.7- 106.9%, with CVs between 1.7 to 7.3%.
The stability of Abbott-85499 in dog plasma was also examined. The results indicated that
Abbott-85499 was stable in dog plasma when stored at -20°C for more than one month.
Abbott-85499 was also stable when subjected to three cycles of freezing and thawing.
Abbott-85499 was stable in plasma stored at room temperature for at least 8.5hours. The
pentafluoroyl benzoyl derivatives of Abbott-85499 and the internal standard were stable in
the reconstitution solution when stored in a refrigerated autosampler tray for up to 57 hours.
Table 1. Summary of Dexmedetomidine Pharmacokinetic Data in Animals
Tmax Cmax t1/2° AUC0-∞ Clp vc Vβ

Species Dose* Route (h) (ng/mL) Cmax/D (h) (ng•h/mL) AUC/D (L/h•kg) (L/kg) (L/kg) Ref.
Rat 20 sc 0.7 1.29 0.08 2.1 3.4 0.20 5.0 1
100 sc 0.6 10.65 0.13 2.0 33.9 0.40 2.6
500 sc 0.7 71.59 0.17 2.0 263.1 0.62 2.0
Rabbit 96 iv 1.83 40.7 0.50 2.1 1.2 6.0 4
Dog 0.2† it 0.009 0.043 nf 0.007 0.04 3
1.2† it 0.09 0.075 0.65 0.124 0.10
8.0† it 1.07 0.134 0.86 1.80 0.22
50 iv 0.68 45.34 1.07 0.9 0.41 0.93 2
50 im 0.6 12.04 0.28 0.85 25.66 0.61
250 im 0.6 160.5 0.76 1.31 428.4 2.03
*Dose = µg dextnedetomidine• HCl/kg; All values expressed as ng of the free base

†
Doses of 2, 12 and 80 µg/day normalized to doses of 0.2, 1.2 and 8 µg/kg/day
nf = unable to calculate plasma elimination half-life; °Harmonic mean
Cmax/D = ng/mL per µg/kg: AUC/D = ng•h/mL per µg/kg
iv = intravenous; sc = subcutaneous; im = intramuscular; it = intrathecal
Table 2. Summary of Pharmacokinetic Parameters for Dexmedetomidine in Rats
No. of Tmax Cmax t1/2° AUC0-∞ CLp

Dose *
Sex Doses Route (h) (ng/mL) Cmax/D (h) (ng•h/mL) AUC/D (L/h•kg) Ref
20 M 1 sc 0.6 1.56 0.09 1.8 3.6 0.21 4.9 1
F 1 sc 0.8 1.01 0.06 2.4 3.3 0.19 5.2
Mean 0.7 1.29 0.08 2.1 3.4 0.20 5.0
100 M 1 sc 0.5 9.89 0.12 2.0 28.6 0.34 3.0 1
F 1 sc 0.7 11.40 0.13 2.0 39.1 0.46 2.2
Mean 0.6 10.65 0.13 2.0 33.9 0.40 2.6
500 M 1 sc 0.9 65.34 0.15 1.9 227.5 0.54 1.9 I
F 1 sc 0.5 77.84 0.18 2.0 298.8 0.71 2.1
Mean 0.7 71.59 0.17 2.0 263.1 0.62 2.0
*Dose = µg dexmedetomidine•HCl per kg; All values expressed as ng of the free base
Cmax/D = ng/mL per µg/kg; AUC/D = ng•h/mL per µg/kg;
° = harmonic mean; sc = subcutaneous
Table 3. Summary of Pharmacokinetic Parameters for Dexmedetomidine in Dogs
No. of Tmax Cmax tl/2° AUC0-∞ Clp Vc v

Dose* Sex Doses Route (h) (ng/mL) Cmax/D (h) (ng•h/mL AUC/D (L/h•kg) (L/kg) (L/kg) Ref.
50 M 1 iv 0.67 46.11 1.09 0.9 0.56 0.91 2
F 1 iv 0.68 44.58 1.05 1.0 0.27 0.96
Mean 0.68 45.34 1.07 0.9 0.41 0.93
50 M 1 im 0.3 13.70 0.32 0.91 27.74 0.66 2
F 1 im 0.8 10.38 0.25 0.83 23.57 0.56
Mean 0.6 12.04 0.28 0.85 25.66 0.61
250 M 1 im 0.4 174.8 0.83 1.14 426.60 2.02 2
F 1 im 0.8 146.2 0.69 1.52 430.10 2.03
Mean 0.6 160.5 0.76 1.31 428.40 2.03
0.2† M Day 1 it 0.008 0.040 nf 0.004 0.02 3
F it 0.009 0.046 nf 0.010 0.05
Mean 0.009 0.043 0.007 0.04
0.2† M Day 22 it 0.011 0.057 nf 0.005 0.03 3
F it 0.014 0.070 nf 0.012 0.06
Mean 0.013 0.063 0.009 0.04
1.2† M Day 1 it 0.090 0.075 0.57 0.104 0.09 3
F it 0.089 0.074 0.77 0.145 0.12
Mean 0.090 0.075 0.65 0.124 0.10
1.2† M Day 22 it 0.081 0.067 0.67 0.115 0.10 3
F it 0.082 0.068 0.61 0.129 0.11
Mean 0.081 0.068 0.64 0.122 0.10
8.0† M Day 1 it 0.93 0.116 0.85 1.61 0.20 3
F it 1.21 0.151 0.86 1.99 0.25
Mean 1.07 0.134 0.86 1.80 0.23
8.0† M Day 22 it 0.95 0.118 0.82 1.66 0.21 3
F it 1.43 0.179 0.78 2.07 0.26
Mean 1.19 0.149 0.80 1.86 0.23
* Dose = µg dexmedetomidine • HCl per kg; All values expressed as ng of the free base; ° - harmonic mean; Cmax/D = ng/mL per µg/kg;
AUC/D =ng•h/mL per µg/kg; nf = unable to calculate plasma elimination half-life; iv = intravenous; im = intramuscular,
it - intrathecal; † = doses of 2, 12 and 80 µg/day normalized to doses of 0.2, 1.2 and 8.0 µg/kg/day
Table 4. Summary of Pharmacokinetic Parameters for Dexmedetomidine in Rabbits
Dose* t1/2 vc Vβ AUC0-∞ CLp

Rabbit No. Sex Route (h) (L/kg) (L/kg) (ng•h/mL) (L/h•kg) AUC/D Ref.
1 F 96/iv 1.27 1.4 4.7 31.6 2.6 0.39 4
2 F 96/iv 2.53 1.4 8.8 33.5 2.4 0.41
3 F 96/iv 2.10 1.2 6.6 37.2 2.2 0.46
4 F 96/iv 1.87 0.8 3.6 60.5 1.3 0.74
Mean 1.83° 1.2 6.0 40.7 2.1 0.50

SD 0.3 2.3 13.4 0.5 0.16
SEM 0.1 1.1 6.7 0.3 0.08
* Dos: = μg dexmedetomidine*HCl per kg

˚ = harmonic mean
AUC/D = ng*h/mL per μg/kg
Table 5. Summary of [3H]Dexmedetomidine Metabolism in Animals and Humans -

Plasma Data
Parameter Rat Rat Dog Dog Human
Dose (μg/kg)* 20, iv 20, sc 20, iv 20, sc 2. iv†
Plasma
Total 3H
Cmax (ng Eq/mL) 2.48 8.98
Tmax. (h) 2.13 6.0
AUC (ng Eq•h/mL) 42.55 28.96 101.81 110.38 22.17
Dexmedetomidine
Cmax (ng/mL) 2.03 4.39
Tmax (h) 0.50 2.0
AUC (ng•h/mL) 2.04 4.53 15.14 19.03 3.26
Metabolites
AUC (ng Eq•h/mL)
Total 3H 32.63 30.48 101.81 110.38 22.17
OH 0.62 0.46 1.01 1.00 nd
COOH 3.04 1.67 5.0 4.58 0.24
G-OH 3.05 1.96 8.37 5.94 0.67
SO3OH 3.63 2.28 7.2 7.67 nd
GS-OH nd nd nd nd nd
M-OH nd nd nd nd nd
G-Dex-1 nd nd nd nd 7.8
N-Me. nd nd nd nd 0.06
G N Mc-OH nd nd nd nd 4.56
N-Me-COOH nd nd nd nd 0.07
H-3 nd nd nd nd 3.48#
Others 20.28 19.60 65.09 72.18 0.66
Reference 5 5 7 7 8
*
Dose = μg dexmedetomidine•HCl per kg
All data expressed as ng or ng Eq of free base
iv = intravenous
sc = subcutaneous
† = 10 minute infusion; nd = not detected
# = corrected for loss of tritium
Table 6. Excretion Data for the [3H]Dexmedetomidine Dose in Animals and Humans
% of the 3H-Dose
Species Dose* Route Sex Duration Urine† Feces Bile Ref.
Rat 20 iv M 3 Days 57.27 40.99 na 5
iv F 3 Days 72.08 26.47 na
iv Mean 64.68 33.73 na
Rat 20 sc M 3 Days 41.35 60.19 na 5

sc F 3 Days 58.81 36.62 na
sc Mean 50.08 48.41 na
Rat 20 iv M 1 Day na na 51.74 30

iv F 1 Day na na 51.42
iv Mean na na 51.58
Rat 20 sc M 1 Day na na 52.22 30

sc F 1 Day na na 38.52
sc Mean na na 45.37
Dog 20 iv M 3 Days 78.14 14.86 na 7

iv F 3 Days 85.01 11.85 na
iv Mean 81.58 13.35 na
Dog 20 sc M 3 Days 82.42 13.47 na 7

sc F 3 Days 83.80 12.41 na
sc Mean 83.11 12.94 na
Human 2# iv M 9 Days 95.17 4.08 na 8

2@ iv M 10 Days 88.84 5.86 na 31
Mean 92.01 4.97 na
*Dose = μg dexmedelomidine•HCl per kg

†= including cage wash, except for humans
#
= 10 minute infusion
@
= 5 minute infusion
na = not analyzed/applicable
iv = intravenous
sc = subcutaneous
Table 7. Summary of Urinary Excretion of [3H]Dexmedetomidine and Metabolites in

Animals and Humans
Parameter Rat Rat Dog Dog Human

Dose* 20, iv 20, sc 20, iv 20, sc 2, iv#
Metabolism
Urine (% Dose)
Total 3H 60.19 41.78 78.97 80.52 93.83
Dex. 0.88 0.40 nd 0.44 nd
OH 3.20 1.99 1.33 2.21 1.11
COOH 8.75 5.79 13.21 11.77 4.80
G-OH 8.32 6.50 10.82 8.06 7.66
SO3OH 9.01 6.09 13.12 15.26 nd
GS-OH nd nd nd nd nd
M-OH 3.34 2.68 nd nd nd
N-Me nd nd nd nd nd
G-N-Me-OH nd nd nd nd 14.51
N-Me-COOH nd nd nd nd 3.76
H-3 nd nd nd nd nd
Others 26.72 18.37 40.50 42.80 28.02
Reference 5 5 7 7 8
*Dose = μg dexmedelomidine•HCl per kg

iv = intravenous
sc - subcutaneous
nd - not detected
#
Table 8. Summary of Fecal and Biliary Excretion of [3H]Dexmedetomidine and

Metabolites in Animals and Humans
Parameter Rat Rat Rat Rat Dog Human

Dose* 20, iv 20, sc 20, iv 20, sc 20, iv 20, sc 2, iv#
Feces (% Dose)
Total 3H 33.23 47.66 na na 10.37 11.46 3.38
Dex. nd nd na na nd nd 0.06
OH 1.92 3.12 na na 0.84 0.91 0.18
COOH 2.61 5.77 na na 1.78 2.02 0.47
G-OH 2.36 3.64 na na nd nd 0.04
SO3OH 1.48 3.04 na na 0.24 0.95 nd
M-OH nd nd na na nd nd nd
GS-OH nd nd na na nd nd 0.09
G-Dex-1 nd nd na na nd nd 0.01
G-Dcx-2 nd nd na na nd nd nd
N-Me nd nd na na nd nd nd
G-N-Me-OH nd nd na na nd nd 0.19
N-Me-COOH nd nd na na nd nd nd
H-3 nd nd na na nd nd 0.06**
Others 24.87 32.10 na na 7.52 7.58 2.28
Bile (% Dose)
Total 3H na na 51.58 45.36 na na na
Dex. na na 0.05 0.05 na na na
OH na na nd nd na na na
COOH na na 1.05 0.60 na na na
G-OH na na 14.96 15.26 na na na
SO3OH na na 2.64 1.77 na na na
GS-OH na na 3.73 3.11 na na na
M-OH na na 0.26 0.37 na na na
G-Dex-1 na na nd nd na na na
G-Dex-2 na na nd nd na na na
G-N-Me-OH na na nd nd na na na
N-Me-COOH na na nd nd na na na
H-3 na na nd nd na na na
Others na na 28.91 24.24 na na na
Reference 5 5 30 30 7 7 8
*Dose = μg dexmedetomidine•HCl per kg; iv = intravenous; sc = subcutaneous; #= 10 minute infusion
nd = not detected; na = not analyzed/not applicable; ** corrected for loss of tritium
Table 9. Summary of Pharmacokinetic and Metabolism Results in Rats Given

[3H]Dexmedetomidine - Plasma Data
Dose* 20, iv 20, sc

Parameter Male Female Mean Male Female Mean
Total 3H
Cmax (ng Eq/mL) 2.12 2.83 2.48
Tmax (h) 0.25 4.0 2.13
AUC0-72 (ng Eq•h/mL) 26.53 58.58† 42.55 22.10 35.82 28.96
Dexmedetomidine
Cmax (ng/mL) 2.28 1.78 2.03
Tmax (h) 0.50 0.50 0.50
AUC0-24 (ng•h/mL) 2.19 1.89 2.04 5.48 3.58 4.53
Metabolites
AUC0-24 (ng Eq•h/mL)
Total 3H 27.23 38.02 32.63 26.92 34.03 30.48
OH 0.52 0.71 0.62 0.18 0.73 0.46
COOH 4.28 1.79 3.04 2.59 0.14 1.67
G-OH 3.46 2.63 3.05 2.25 1.67 1.96
SO3OH 0.42 6.84 3.63 nd 4.55 2.28
GS-OH nd nd nd nd nd nd
M-OH nd nd nd nd nd nd
N-Me nd nd nd nd nd nd
M-2 0.90 1.05 0.98 0.86 0.86 0.86
M-5 4.30 3.26 3.78 3.12 2.81 2.97
M-6 5.90 10.17 8.04 5.57 9.16 7.37
M-7 0.94 2.74 1.84 1.05 3.62 2.34
M-8 1.05 3.32 2.19 1.59 2.55 2.07
Others 3.31 3.61 3.46 4.23 3.76 4.00
Reference 5 5 5 5
*
All values expressed as ng or ng Eq of the base/mL
iv - intravenous
sc = subcutaneous
†
n=1
nd = not detected
Table 10. Distribution of Radioactivity in Tissues of Rats after an Intravenous Dose of

[3H]Dexmedetomidine
Male Female
Cmax Tmax Cmax Tmax
Matrix (ng Eq base/g)* (h) (ng Eq base/g)* (h)
Liver 223.3 2.0 197.1 1.0
Adrenals 207.2 12.0 382.3 4.0
Lungs 182.7 0.25 230.1 0.5
Kidneys 128.6 0.5 92.2 0.25
Small Intestine† 126.9 4.0 156.5 4.0
Large Iniestine† 112.5 6.0 62.3 6.0
Stomach† 86.3 2.0 105.7 2.0
Pancreas 65.5 0.5 77.5 0.5
Brain 22.3 0.25 22.5 0.25
Testes 23.5 2.0 - -
Prostate 15.3 0.5 - -
Ovaries - - 22.3 0.25
Uterus - - 11.8 0.25
Plasma 2.9 0.25 4.5 2.0
Reference 14 14 14 14
Dose = 20 μg dexmedetormdine•HCl per kg

*rounded to a single decimal place
†including contents
Table 11. Summary of Metabolism Results in Rats Given [3H]Dexmedetomidine - Urine

Data†
Dose* 20, iv 20, sc

Metabolism
Urine (% of Dose)
Total 3H 51.46 68.92 60.19 32.44 51.12 41.78
Dex 0.78 0.97 0.88 0.53 0.27 0.40
OH 3.28 3.12 3.20 2.05 1.92 1.99
COOH 10.62 6.88 8.75 7.05 4.52 5.79
G-OH 8.96 7.67 8.32 5.67 7.32 6.50
SO3OH 0.94 17,07 9.01 1.19 10.99 6.09
M-OH 0.06 6.62 3.34 0.51 4.84 2.68
M-2 4.15 5.07 4.61 2.46 330 2.88
M-5 7.24 7.23 7.24 4.04 5.76 4.90
Others 15.44 14.30 14.87 8.96 12.21 10.59
Reference 5 5 5 5
*
Dose =μg dexmedetomidine•HCl per kg
nd - not detected
iv = intravenous
sc = subcutaneous
†
= 0-48 hour urine
Table 12. Summary of Metabolism Results in Rats Given [3H]Dexmedetomidine - Feces

Data†
Dose* 20, iv 20, sc

Metabolism
Feces (% of Dose)
Total 3H 40.41 26.05 33.23 59.25 36.07 47.66
Dex nd nd nd nd nd nd
OH 2.46 1.37 1.92 4.10 2.14 3.12
COOH 3.24 1.98 2.61 8.88 2.65 5.77
G-OH 3.21 1.50 2.36 5.44 1.84 3.64
SO3OH 0.61 2.35 1.48 1.45 4.63 3.04
M-OH rd nd nd nd nd nd
M-2 1.18 1.19 1.19 1.38 1.38 1.38
M-5 7.09 4.35 5.72 9.00 6.31 7.66
Others 22.61 13.31 17.96 29.00 17.13 23.07
Reference 5 5 5 5
*
Dose = μg de*mcdetomidine•HCl per kg
nd - not detected
iv - intravenous
sc = subcutaneous
†
= 0-48 hour feces
Table 13. Summary of Metabolism Results in Rats Given [3H]Dexraedetomidine - Bile

Data†
Dose* 20, iv 20, sc

Metabolism
Bile (% of Dose)
Total 3H 51.75 51.41 51.58 52,22 38.50 45.36
Dex 0.09 nd 0.05 0.10 nd 0.05
OH nd nd nd nd nd nd
COOH 1.27 0.82 1.05 0.99 0.20 0.60
G-OH 15.91 14,00 14.96 18.17 12.34 15.26
SO3OH 1.31 3.97 2.64 0.85 2.68 1.77
GS-OH 1.00 6.46 3.73 0.85 5.36 3.11
M-OH 0.24 0.27 0.26 0.15 0.58 0.37
M-2 9.88 7.92 8.90 8.65 5.61 7.13
M-5 0.40 0.51 0.46 0.11 0.40 0.26
Others 21.65 17.46 19.56 22.37 11.34 16.86
Reference 30 30 30 30
*
nd = not detected
iv = intravenous
sc = subcutaneous
†
= 0-24 hour bile
Table 14. Summary of Pharmacokinetic and Metabolism Results in Dogs Given

Dose* 20, iv 20, sc

Total 3H
Cmax (ng Eq/mL) 9.33 9.2 8.89
Tmax (h) 4.0 6.0 6.0
AUC0-120 (ng Eq•h/mL) 96.76 106.85 101.81 109.39 111.37 110.38
Dexmedefomidine
Cmax (ng/mL) 5.51 3.58 4.39
Tmax (h) 2.0 4.0 2.00
AUC0-12 (ng•h/mL) 14.79 15.50 15.14 20.53 17.53 19.03
Metabolites
AUC (ng Eq•h/mL)
Total 3H 96.76 106.85 101.81 109.39 111.37 110.38
OH 0.80 1.22 1.01 1.05 0.94 1.00
COOH 3.98 6.02 5.00 4.12 5.03 4.58
G-OH 8.21 8.54 8.37 6.10 5.77 5.94
SO3OH 5.93 8.47 7.20 8.03 7.31 7.67
D-l nd nd nd nd nd nd
D-2 3.07 3.34 3.20 1.98 3.94 2.96
D-3 nd nd nd nd nd nd
D-4 8.51 5.14 6.83 7.66 4.37 6.01
D-6 4.36 3.49 3.93 4.52 3.60 4.06
D-7 0.66 1.81 1.23 4.24 2.69 3.46
Others 46.45 53.32 49.91 51.16 60.19 55.69
Reference 7 7 7 7
*
All values expressed as ng or ng Eq of the base/mL
iv = intravenous
sc = subcutaneous
nd = not detected
Table 15. Summary of Metabolism Results in Dogs Given [3H]Dexmedetomidine - Hour

Urine Data†
Dose* 20, iv 20, sc

Metabolism
Urine (% of Dose)
Total 3H 74.62 83.31 78.97 79.52 81.51 80.51
Dex nd nd nd nd 0.87 0.43
OH 0.85 1.80 1.32 2.86 1.56 2.21
COOH 11.44 14.98 13.21 11.52 12.02 11.77
G-OH 11.86 9,77 10.81 9.24 6.87 8.06
SO3OH 13.86 12.38 13.12 16.45 14.06 15.25
D-l 8.32 9.68 9.00 8.80 10.96 9.88
D-2 6.57 8.46 7.52 6.40 7.11 6.76
D-3 5.32 6.92 6.12 6.44 6.76 6.60
D-4 7.77 4.85 6.31 6.79 5.79 6.29
D-6 2.73 1.08 1.91 2.85 2.08 2.46
Others 5.91 13.39 9.65 8.17 13.44 10.80
Reference 7 7 7 7
*
iv = intravenous
sc = subcutaneous
nd = not detected
†
= 0-48 hour urine
Table 16. Summary of Metabolism Results in Dogs Given [3H]Dexmedetomidine - Feces

Data †
Dose* 20, iv 20, sc

Metabolism
Feces (% of Dose)
Total 3H 12.86 7.87 10.37 12.96 9.96 11.46
Dex nd nd nd nd nd nd
OH 1.20 0.47 0.83 1.05 0.77 0.91
COOH 2.16 1.40 1.78 2.55 1.49 2.02
G-OH nd nd nd nd nd nd
SO3OH 0.47 nd 0.24 0.85 1.05 0.95
D-l nd nd nd nd nd nd
D-3 1.50 1.88 1.69 1.28 0.90 1.09
D-5 2.63 1.52 2.08 3.19 2.58 2.89
Others 4.90 2.60 3.75 4.04 3.16 3.60
Reference 7 7 7 7
*
iv = intravenous
sc - subcutaneous
nd = not detected
†
= 0-48 hour feces
Table 17. Summary of Pharmacokinetic and Metabolism Results in Humans Given

Dose* 2.0†
Parameter Males
Total 3H
AUC0-24 (ng Eq•h/mL) 22. 17
Dexmedetomidine
AUC0-24 (ng Eq•h/mL) 3.26
Metabolites
AUC0-24 (ng Eq•h/mL)
OH nd
COOH 0.24
G-OH 0.67
SO3OH nd
GS-OH nd
M-OH nd
G-Dex-1 7.80
G-Dex-2 1.37
N-Me 0.06
N-Me-OH nd
G-N-Me-OH 4.56
H-2 0.54
H-3 3.48#
N-Me-COOH 0.07
Others 0.12
Reference 8
*
All values expressed as ng or ng Eq of the base/g
nd = not detected
†
# - corrected for loss of tritium

[3H]Dexmedetomidine - Urine Data
Dose* 2.0†
Parameter Males
Metabolism
Urine (% of Dose)
Total 3H 93.83
Dex nd
OH 1.11
COOH 4.80
G-OH 7.66
SO3OH nd
GS-OH nd
M-OH nd
G-Dex-l 19.56
G-Dex-2 14.43
N-Me nd
N-Me-OH nd
G-N-Me-OH 14.51
H-2 nd
H-3 nd
N-Me-COOH 3.76
Others 28.02
Reference 8
*
nd = not detected
†

[3H]Dexmedetomidine - Feces Data
Dose* 2.0†
Parameter Males
Metabolism
Feces (%. of Dose)
Total 3H 3.38
Dex 0.06
OH 0.18
COOH 0.47
G-OH 0.04
SO3OH nd
M-OH nd
GS-OH nd
G-Dex-1 0.09
G-Dex-2 0.01
N-Me nd
N-Me-OH nd
G-N-Me-OH 0.19
H-2 nd
H-3 0.06#
N-Me-COOH nd
Others 2.28
Reference 8
*
nd = not detected
†
# = corrected for loss of tritium
Figure 1. Proposed Dexmedetomidine Metabolic Pathway
Glucuronide
Carboxy N-Methyl N-Methyl O-Glucuronide
[N-Me-COOH] [G-N-Me-OH] Conjugation

Oxidation
3-Hydroxy N-Methyl
[N-Me-OH]
Hydroxidation
N-Methyl O-Glucuronide
N-Methyl
[N-Me]
Glucuronide
N-Methylation
G-Dex 1
Hydroxidation Conjugation
[H-3] Dexmedetomidine
Hydroxidation
Glucuronide G-Dex 2
3-Hydroxy-Dex
[OH]
Oxidation Conjugation
Glucuronide (G-OH)
Sulfate (SO3OH))
Carboxy Dex Glucathione (GS-OH)
[COOH] [Text: Illegible](M-OH)
5.3.11 Summaries of Individual Reports
5.3.11.1. Hui YH. Abbott-85499 Drug Metabolism Report No. 34 - Plasma

Concentrations of Dexmedetomidine Following Subcutaneous Dosing in
Rat (Protocol V96-557). Abbott Laboratories Division 46 Report No.
R&D/97/617, January 1998.
Title: Plasma Concentrations of Dexmedetomidine following Subcutaneous Dosing in Rat

(Protocol V96-557).
Objective: To characterize the pharmacokinetics of dexmedetomidine at three separate

subcutaneous doses in rat.
Investigator, Study Site and Dates: The study was conducted in the Toxicology
Department of Abbott Laboratories, Abbott Park, IL by members of the Experimental
Toxicology Group. The study director was Kennan C. Marsh, Ph.D.; the study monitor was
Mary Helgren, B.S. The study was completed on October 27, 1997.
Study Design: The study was of a parallel design, with three groups of rats. Each treatment
group contained three male and three female rats. Animals received a single subcutaneous
dose of dexmedetomidine hydrochloride corresponding to 20 (T1),
100 (T2) or 500 (T3) μg/kg.
Subjects: A total of eighteen Sprague-Dawley rats, 9 male and 9 female, approximately

eight to ten weeks of age (Charles River Laboratories, Inc., Portage, MI), were utilized in
Protocol V96-557. Animals were acclimated for at least seven days prior to dosing.
Food and water were provided ad libitum.
Dose Groups and Dosage Administration: Dexmedetomidine hydrochloride (Abbott-

85499.1, lot # 295260-0-AX) was obtained from the Abbott Drug Sample Room. A
Certificate of Analysis was provided by Orion-Farmos, Turku, Finland. Solutions of
dexmedetomidine hydrochloride were prepared at a concentration appropriate for a 1.0
mL/kg dose volume in each treatment group. The solutions of dexmedetomidine
hydrochloride were prepared in normal saline (0.9% sodium chloride for injection USP).
Groups of rats received a 20 (T1), 100 (T2) or 500 (T3) μg/kg dose. A 20 mL sample of each
of the three dose solutions was submitted to the International Development Centre, Abbott
Laboratories, Ltd., Queensborough, Kent, UK for analysis of dexmedetomidine
hydrochloride concentrations.
Blood Collection and Analysis: Heparinized blood samples (~0.4 mL/sample) were
obtained from each rat 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12 and 24 hours after drug
administration in each of the three treatment groups. The samples were mixed and placed in
an ice bath upon collection. The blood samples were centrifuged at approximately 13,000
rpm for ~3 minutes under refrigerated conditions (2-5°C; the resulting plasma was frozen in
an appropriately labeled vial. Dexmedetomidine plasma concentrations were determined at
Abbott Laboratories, Department 46W, Abbott Park, IL, using a validated gas
chromatographic (GC) with mass spectrometric (MS) detection procedure under GLP
conditions.
Pharmacokinetics and Statistics: The dexmedetomidine plasma concentration (in ng

base/mL) of each sample was calculated by weighted (1/C) least squares linear regression
analysis of the peak area ratio (parent/internal standard) of the spiked rat plasma standards
versus concentration. Pharmacokinetic parameters for dexmedetomidine were estimated by
model independent methods. The maximum plasma concentration (Cmax) and the time to
reach the maximum plasma concentration (T max) were read directly from the observed
plasma concentration-time data. The plasma elimination rate constant (β) was estimated from
the log-linear regression of the terminal plasma concentrations as a function of time after
dosing; the plasma elimination half-life was calculated as t1/2 = 1n 2/β. The area under the
plasma concentration-time curve from 0 to t hours (time of the last measurable plasma
concentration) after dosing (AUC0-t) was calculated using the linear trapezoidal rule. The
residual area extrapolated to infinity, determined as the final measured plasma concentration
(Ct) divided by the terminal elimination rate constant (β), was added to AUC0-t to produce
the total area under the curve (AUC0-∞). The dose-normalized area under the curve was
estimated from AUC0-∞/dose. Apparent plasma clearance (CLp) was determined as the
reciprocal of the dose-normalized AUC∞. Samples with BQL (below quantitation limit)
values were mathematically treated as 0 ng/mL.
Results: Mean (±SD) pharmacokinetic parameters for dexmedetomidine after a single

subcutaneous dose in rat are summarized in the following table:
t1/2 Cmax Tmax AUC0-∞ CLp

Dose† Sex (hr)˚ (ng/mL) Cmax/D (hr) (ng•hr/mL) AUC/D (L/hr•kg)
20 M 1.8 1.56(0.76) 92.1(44.8) 0.6(0.4) 3.6(0.6) 209.6(37.1) 4.9(0.9)
F 2.4 1.01(0.42) 59.8(24.8) 0.8(0.3) 3.3(0.5) 195.6(29.8) 5.2(0.9)
Mean 2.1 1.29(0.62) 75.9(36.9) 07(0.3) 3.4(0.5) 202.6(31.1) 5.0(0.8)
100 M 2.0 9.89(1.35) 116.9(15.9) 0.5(00) 23.6(4.7) 338.5(55.3) 3.0(0.5)

F 2.0 11.40(0.73) 134.8(8.6) 0.7(0.3) 39.1(3.0) 462.5(35.1) 2.2(0.2)
Mean 2.0 10.65(1.27) 125.9(15.1) 0.6(0.2) 33.9(6.7) 400.5(79.5) 2.6(0.6)
500 M 1.9 65.34(13.15) 154.5(31.1) 0.9(0.6) 227.5(48.1) 537.8(113.6) 1.9(0.4)

F 2.0 77.84(0.98) 184.0(2.3) 0.5 (0.4) 298.8(171.7) 706.3(405.9) 2.1(1.7)
Mean 2.0 71.59(10.79) 169.3(25.5) 0.7(0.5) 263.1(119.3) 622.0(282.1) 2.0(1.1)
†
Dose in μg dexmedetomidine•HCl per kg; Sex = M (male, n=3), F (female, n=3) or mean (M/F, n=6).
Units were as follows: Cmax/D (pg/mL per μg/kg): AUC/D (pg*hr/mL per g/kg): ˚ harmonic mean
Conclusions: Dexmedetomidine was rapidly absorbed (Tmax <1 hour) and eliminated (t1/2 - 2
hours) following subcutaneous dosing in rat. Peak plasma concentrations averaged 1.29 ±
0.62, 10.65 ± 1.27 and 71.59 ± 10.79 ng/mL following a single 20, 100 or 500 μg/kg
subcutaneous dose, respectively. Area under the curve values averaged 3.4 ± 0.5, 33.9 ± 6.7
and 263.1 ± 119.3 ng•hr/mL in the same animals. Dexmedetomidine pharmacokinetics
appeared to be non-linear, with greater than proportional increases in both peak plasma
concentration and area under the curve observed over the 20-500 μg/kg dosing interval in
this study. Plasma clearance decreased with increasing dose averaging 5.0 ± 0.8, 2.6 ± 0.6
and 2.0 ±1.1 L/hr•kg in the 20,100 and 500 μg/kg dose groups, respectively. Peak plasma
concentrations and AUC values were slightly higher in female rats in the 100 and 500 μg/kg
dose groups; due to the small number of animals in this study the statistical significance of
this trend could not be determined.

Concentrations of Dexmedetomidine Following a Single IV or IM Dose in
Dog (Protocol V96-556). Abbott Laboratories Division 46 Report No.
R&D/97/615, January 1998.
Title: Plasma Concentrations of Dexmedetomidine following a Single IV or IM Dose in Dog

(Protocol V96-556)
Objective: To characterize the pharmacokinetics of dexmedetomidine following single

intravenous or intramuscular doses in dog.
Investigator, Study Site and Dates: The study was conducted in the Toxicology
Department of Abbott Laboratories, Abbott Park, IL, by members of the Experimental
Toxicology Group. The study was directed by Kennan C. Marsh, Ph.D.; the study monitor
was Mary Helgren, B.S. The study was completed on September 28, 1997.
Study Design: The study was of a parallel design, with three groups of beagle dogs. Each
group contained three male and three female dogs. The first group (T1) received a single 50
μg/kg IV dose administered as a slow bolus in a cephalic vein over 1-2 minutes. The second
group (T2) received a single 50 μg/kg IM dose in the muscle of the thigh. The third group
(T3) received a single 250 μg/kg IM dose in a similar site.
Subjects: A total of eighteen beagle dogs, 9 male and 9 female, approximately 6-24 months
of age and 10 kg from Marshall Farms, North Rose, NY, were utilized in V96-556. Animals
were acclimated for at least seven days prior to dosing.

85499.1, Lot # 295260-0-AX) was obtained from Abbott Drug Sample Room. Compound
Certificate of Analysis was provided by Orion-Farmos, Pharmaceuticals, Finland. Dosing
solutions for the T1 group were prepared by dissolving 12.1 mg of the solid drug with 60.5
mL of 0.9% Sodium Chloride for Injection USP, to a concentration of 200 μg/mL for a 50
μg/kg IV dose (0.25 mL/kg) in each dog. Dosing solutions for the T2 group were prepared by
dissolving 10.7 mg of the solid drug with 53.5 mL of 0.9% Sodium Chloride for Injection
USP, to a concentration of 200 μg/mL for a50 μg/kg IM dose (0.25 mL/kg) in each dog.
Dosing solutions for the T3 group were prepared by dissolving 50.3 mg of the solid drug with
50.3 mL of 0.9% Sodium Chloride for Injection USP, to a concentration of 1000 μg/mL for a
250 μg/kg IM dose (0.25 mL/kg) in each dog. A 20 mL sample of each of the three dose
solutions was submitted to the International Development Center, Abbott Laboratories, Ltd.,
Queensborough, Kent, UK for analysis of dexmedetomidine hydrochloride concentrations.
Blood Collection and Analysis: Heparinized blood samples (approximately 4 mL) were
obtained from all animals in each group prior to dosing and 0.1 (IV only), 0.25, 0.5, 1, 1.5, 2,
3, 4, 6, 9, 12 and 24 hours after drug administration. The samples were mixed and placed in
an ice bath upon collection. The blood samples were centrifuged at approximately 2500 rpm
for 10 minutes under refrigerated conditions (2-5°C); the resulting plasma was frozen in an
appropriately labeled vial. Dexmedetomidine plasma concentrations were determined at
conditions.

analysis of the peak area ratio (parent/internal standard) of the spiked plasma standards
versus concentration. Pharmacokinetic parameters for dexmedetomidine were estimated by
model independent methods. The maximum plasma concentration (Cmax) and the time to
reach the maximum plasma concentration (T max) were read directly from the observed
plasma concentration-time data. The plasma elimination rate constant (β) was estimated from
an open one compartment or two compartment model using NONLIN84; the plasma
elimination half-life was calculated as t1/2 = 1n 2/β. The area under the plasma concentration-
time curve from 0 to t hours (time of the last measurable plasma concentration) after dosing
(AUC0-t) was calculated using the linear trapezoidal rule. The residual area extrapolated to
infinity, determined as the final measured plasma concentration (Ct) divided by the terminal
elimination rate constant (β), was added to AUC0-t to produce the total area under the curve
(AUC0-∞). The dose normalized area under the curve was estimated from AUC0-∞/dose.
Apparent volume of distribution (Vc) was calculated using the dose in μg base/kg divided by
the extrapolated initial plasma concentration (Co) following intravenous administration.
Apparent plasma clearance (CLp) was determined as the reciprocal of the dose normalized
AUC∞. The terminal phase volume of distribution (Vβ) values were measured using CLp
divided by the terminal elimination rate constant (β). Samples with BQL (below quantitation
limit) values were mathematically treated as 0 ng/mL.
Results: Mean (±SD) pharmacokinetic parameters for dexmedetomidine after intravenous

and intramuscular dosing in beagle dog are summarized below:
Mean (±SD) Dexmedetomidine Pharmacokinetic Parameters

50 μg/kg Intravenous Dose
Dose† Vc Vβ CLp t1/2
(Hg/kg) Sex (L/kg) (L/kg) (L/hr•kg) (hr)° AUC∞ AUC/D
50 M 0.56 (0.04) 0.91 (0.18) 0.9 (0.0) 0.67 46.11 (2.00) 1.09(0.05)
F 0.27 (0.10) 0.96 (0.19) 1.0 (0.2) 0.68 44.58 (8.06) 1.05 (0.19)
Mean 0.41 (0.18) 0.93 (0.16) 0.9 (0.1) 0.68 45.34 (5.32) 1.07(0.13)
50 or 250 μg/kg Intramuscular Dose
Dose† Cmax Tmax t1/2

(μg/kg) Sex (ng/mL) Cmax/D (hr) (hr)° AUC AUC/D F(%)
50 M 13.70(1.20) 0.32(0.03) 0.3(0.1) 0.91 27.74(1.39) 0.66(0.03) 61.2(3.1)
F 10.38(2.73) 0.25(0.06) 0.8(0.3) 0.83 23.57(4.56) 0.56(0.11) 52.0(10.1)
Mean 12.04(2.62) 0.28(0.06) 0.6(0.3) 0.85 25.66(3.78) 0.61(0.09) 56.6(8.3)
250 M 174.8(28.9) 0.83(0.14) 0.4(0.1) 1.14 426.6(94.7) 2.02(0.45) 188(42)
F 146.2(49.0) 0.69(0.23) 0.8(0.7) 1.52 430.1(124.5) 2.03(0.59) 190(55)
Mean 160.5(39.2) 0.76(0.19) 0.6(0.5) 1.31 428.4(98.9) 2.03(0.47) 189(44)
† doses in μg dexmedetomidine•HCl per kg; M (male, n=3), F (female, n=3) or Mean (M/F, n=6).
Units were as follows: Cmax/D (ng/mL per μg/kg); AUC0-∞(ng•hr/mL); AUC/D (ng•hr/mL per (μg/kg).
Bioavailability estimated from the 50 μg/kg intravenous dose; ° harmonic mean
Conclusions: Dexmedetomidine was rapidly eliminated following a 50 μg/kg intravenous

dose in dog with a mean apparent half-life of 0.68 hours. Plasma clearance values averaged
0.9 L/hr•kg with a steady-state volume of distribution of 0.9 L/kg (Vβ). The plasma
elimination half-life was slightly longer following intramuscular dosing, averaging 0.85 and
1.31 hours following a 50 or 250 μg/kg dose, respectively. Dexmedetomidine
pharmacokinetics appeared to be non-linear, with greater than proportional increases in both
peak plasma concentration and area under the curve following the 50 and 250 μg/kg
intramuscular dosing. Peak plasma concentrations averaging 12.04 ± 2.62 ng/mL following
the 50 μ.g/kg intramuscular dose increased to 160.5 ± 39.2 ng/mL in the 250 μg/kg
intramuscular dose group. Area under the curve values increased in a similar non-linear
fashion, averaging 25.7 ±3.8 and 428.4 ± 98.9 ng•hr/mL in the 50 and 250 μg/kg IM dose
groups, respectively. Dexmedetomidine peak plasma concentrations and AUC values for the
male dogs were similar to or slightly higher than those in the female subpopulation in each
of the dose groups.
5.3.11.3 Hui YH, Marsh K. Abbott-85499 Drug Metabolism Report No. 5 - Plasma
Concentrations of Abbott-85499 (Dexmedetomidine) following Repeat
Intrathecal Administration in Dog (Protocol TB95-224). Abbott
Laboratories Division 46 Report No. R&D/96/074, April 1996.
Title: Plasma Concentrations of Abbott-85499 (Dexmedetomidine) following Repeat

Intrathecal Administration in Dog (Protocol TB95-224)
Objective: To characterize the pharmacokinetics of dexmedetomidine following repeat

intrathecal dosing in beagle dog.
Investigator, Study Site and Dates: The study was conducted under the direction of L. A.
Gallenberg, Ph. D., Department of Toxicology, Abbott Laboratories, Abbott Park, IL, at Bio-
Research Laboratories, Ltd.,. Senneville, Quebec, Canada (Project 54322).
Study Design: The study was of a parallel design, with four groups of dogs. Groups 2 and 3
contained three male and three female dogs; Group 1 and Group 4 contained two additional
dogs of each sex as recovery animals.
Subjects: A total of thirty-two beagle dogs, 16 male and 16 female, approximately 5-7
months of age and 6-10 kg were utilized in TB95-224.
Dose Groups and Dosage Administration: Dexmedetomidine hydrochloride was provided

as an ampoule containing a 200 μg/mL solution 0.9% Sodium Chloride.
Dosing solutions were prepared by diluting the clinical supplies with 0.9% Sodium Chloride
for Injection USP, to concentrations appropriate for a 0.5 mL dose in each dog in all dose
groups. Groups of dogs received a 0 (Group 1), 2 (Group 2), 12 (Group 3) or 80 (Group 4)
μg intrathecal dose administered once daily for twenty-eight consecutive days.
obtained from all animals in all groups approximately 0.25, 0.5, 1, 2, 4 and 6 hours after
dosing on Day 1 and Day 22. The plasma collected from each sample was frozen in an
appropriately labeled vial. Dexmedetomidine plasma concentrations were determined at
conditions.
Pharmacokinetics and Statistics: The dexmedetomidine plasma concentrations (in pg

base/mL) on Day 1 and Day 22 were normalized to nominal dosages of 0.2, 1.2 and 8.0μg
Abbott-85499•HCl/kg/day based on the most recently available body weight for each dog.
The plasma drug concentration of each sample was calculated by weighted (1/C) least
squares linear regression analysis of the peak area ratio (parent/internal standard) of the
spiked plasma standards versus concentration. Pharmacokinetic parameters for
dexmedetomidine were estimated by model-independent methods. The maximum plasma
concentration (Cmax) and the time to reach the maximum plasma concentration (Tmax) were
read directly from the observed plasma concentration-time data. The plasma elimination rate
constant (β) was estimated from the log-linear regression of the terminal plasma
concentrations as a function of time after dosing; the plasma elimination half life was
calculated as t1/2 = 1n 2/β. The area under the plasma concentration-time curve from 0 to t
hours (time of the last measurable plasma concentration) after dosing (AUC0-t) was
calculated using the linear trapezoidal rule for the plasma-time profiles. The residual area
extrapolated to infinity, determined as the final measured plasma concentration (Ct) divided
by the terminal elimination rate constant (β), was added to AUC0-t to produce the total area
under the curve (AUC0-∞).
Results: Mean (±SD) pharmacokinetic parameters for dexmedetomidine after multiple

intrathecal dosing in beagle dog on both Day 1 and Day 22 are summarized in the following
table.
Dexmedetomidine Mean (±SD) Pharmacokinetic Parameters

†
Dose Cmax t1/2†
(g/kg) D* S* (pg/mL) Cmax/D (hr) AUC AUC/D
0.2 1 M 7.9 (7.5) 39.7 (37.5) nf 3.7 (3.2) 18.6(16.1)
F 9.2 (8.2) 46.1 (40.8) nf 10.4 (9.2) 51.8 (45.9)
M/F 8.6 (7.0) 42.9 (35.2) nf 7.0 (7.2) 35.2 (35.8)
22 M 11.4 (1.0) 57.0(5.1) nf 5.2 (1.8) 25.9 (8.8)

F 14.0(1.6) 69.9 (7.8) nf 12.5(4.7) 62.7 (23.5)
M/F 12.7(1.8) 63.4 (9.2) nf 8.9 (5.1) 44.3 (25.6)
1.2 1 M 89.8 (49.0) 74.8 (40.8) 0.57 103.6 (39.5) 86.3 (32.9)
F 89.2 (24.8) 74.3 (20.7) 0.77 144.9 (40.2) 120.8 (33.5)
M/F 89.5 (34.8) 74.6 (29.0) 0.65 124.3 (42.2) 103.6 (35.2)
22 M 80.9 (21.5) 67.4 (17.9) 0.67 114.9(17.1) 95.8 (14.3)

F 81.6 (16.0) 68.0 (13.4) 0.61 129.4 (25.2) 107.8 (21.0)
M/F 81.2 (17.0) 67.7(14.1) 0.64 122.1 (20.8) 101.8(17.3)
8.0 1 M 927.9 (316.6) 116.0 (39.6) 0.85 1610.2(264.6) 201.3 (33.1)

F 1207.8 (593.5) 151.0 (74.2) 0.86 1986.8(643.1) 248.3 (80.4)
M/F 1067.9 (472.9) 133.5 (59.0) 0.86 1798.5 (504.3) 224.8 (63.0)
22 M 945.7 (401.6) 118,2 (50.2) 0.82 1658.7(602.9) 207.3 (75.4)

F 1429.5 (482.2) 178.7 (60.3) 0.78 2068.4 (312.0) 258.5 (39.0)
M/F 1187.6 (490.0) 148.5 (61.2) 0.80 1863.5 (501.4) 232.9 (62.7)
† doses of 2, 12 and 80 μg/day normalized to nominal doses of 0.2,1.2 and 8.0 μg/kg/day.
* D = Study Day 1 or Day 22; S = M(ale), F(emale) or mean (M/F).
ǂ harmonic mean.
Units were as follows: Cmax/D (pg/mL per μg/kg/day); AUC0-∞(pg•hr/mL); AUC/D
(pg•hr/mL per μg/kg/day).
nf - Unable to calculate plasma elimination half life.
Conclusions: Mean peak concentrations of dexmedetomidine following intrathecal

administration in dog ranged from values at or near the limit of quantitation (10 pg/mL) in
the low dose group (0.2 μg/kg) to values of approximately 1000 pg/mL in the 8.0 μg/kg dose
group. Dexmedetomidine pharmacokinetics appeared to be non-linear with greater than
proportional increases in both peak plasma concentration and area under the curve observed
in the 0.2, 1.2 and 8.0 μg/kg dose groups. Dexmedetomidine plasma elimination half-lives
averaged 0.6 hours in the 1.2 μg/kg/day dose group, increasing slightly to 0.8-0.9 hours in
the 8.0 μg/kg/day dose group following intrathecal administration in beagle dog. Area under
the curve values averaged 7.0 ± 7.2, 124.3 ±42.2 and 1798.5 ± 504.3 pg•hr/mL in the 0.2, 1.2
and 8.0 μg/kg/day dose groups, respectively, on the first day of dosing; area under the curve
values did not change with multiple dosing, averaging 8.9 ± 5.1, 122.1 ±20.8 and 1863.5 ±
501.4 pg•hr/mL for the same dose groups on Day 22. With the exception of the 1.2
μg/kg/day peak plasma concentrations, the Cmax and AUC values for the female dogs were
slightly higher than those in the male subpopulation in each of the dose groups.

Concentrations of Dexmedetomidine Following Intravenous Dosing in
Rabbit (Protocol V96-558). Abbott Laboratories Division 46 Report No.
R&D/97/616, January 1998.
Title: Plasma Concentrations of Dexmedetomidine following Intravenous Dosing in Rabbit

(Protocol V96-558)
Objective: To characterize the pharmacokinetics of dexmedetomidine following a single 96

μg/kg intravenous dose in rabbit.
Investigator, Study Site and Dates: The study was conducted in the Drug Safety
Evaluation Department of Abbott Laboratories, Abbott Park, IL, by members of the
Experimental Toxicology Group. The study was under the direction of Kennan C. Marsh,
Ph.D.; the study monitor was Mary Helgren, B.S. The animals were dosed on April 23, 1997;
pharmacokinetic analysis was completed on October 8, 1997.
Study Design: The study used a single groups of four female rabbits. Each rabbit received a
single 96 μg/kg intravenous dose of dexmedetomidine hydrochloride, administered as a slow
bolus in a marginal ear vein.
Subjects: Four female New Zealand White Rabbits, that were at least five months of age
(Covance Research Products, Kalamazoo, MI) were utilized in Protocol V96-558. The
animals were acclimated for at least seven days prior to dosing. Food and water were
provided ad libitum.

85499.1, Lot # 295260-0-AX) was obtained from the Abbott Drug Sample Room. A
Certificate of Analysis was provided by Orion-Farmos, Finland. A solution of
dexmedetomidine hydrochloride at a concentration of 95.9 μg/mL was prepared by
dissolving a weighed amount of the solid in 0.9% Sodium Chloride for Injection USP, for a 1
mL/kg intravenous dose in each rabbit. A 20 mL sample of the solution was submitted to the
International Development Centre, Abbott Laboratories, Ltd., Queensborough, Kent, UK for
analysis of dexmedetomidine hydrochloride concentrations.
obtained from an alternative ear vein of all rabbits 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 9, and 12 hours
after dosing. The samples were mixed and placed in an ice bath upon collection. The blood
samples were centrifuged at approximately 2500 rpm for 10 minutes under refrigerated
conditions (2-5°C); the resulting plasma was frozen (<-15°C) in an appropriately labeled
vial. Dexmedetomidine plasma concentrations were determined at Abbott Laboratories,
Department 46W, Abbott Park, IL, under the direction of Dr. Yu-Hua Hui, using a validated
gas chromatographic (GC) with mass spectrometric (MS) detection procedure under GLP
conditions.

analysis of the peak area ratio (parent/internal standard) of the spiked rabbit plasma
standards versus concentration. The plasma elimination rate constant (β) was estimated from
open two compartmental model using NONLEN84; the plasma elimination half-life was
calculated as t1/2 = 1n 2/β. The area under the plasma concentration-time curve from 0 to t
hours (time of the last measurable plasma concentration) after dosing (AUC0-t) was
calculated using the linear trapezoidal rule for the plasma-time profiles.
The residual area extrapolated to infinity, determined as the final measured plasma con-
centration (Ct) divided by the terminal elimination rate constant (β), was added to AUC0-t to
produce the total area under the curve (AUC0-∞). Apparent volume of distribution (Vc) was
calculated using the dose in μg base per kg divided by the extrapolated initial plasma
concentration (Co) following intravenous administration. Clearance (CLp) was determined
using the reciprocal of the dose normalized AUG∞. The terminal phase volume of
distribution (Vβ) was calculated as the CLp divided by the terminal elimination rate constant
(β).
Results: The mean pharmacokinetic parameters for dexmedetomidine after a single

intravenous dose in rabbit are summarized in the following table:
Dexmedetomidine Mean (±SD, n=4) Pharmacokinetic Parameters

†
Dose vc vβ CLp tl/2 AUC0-∞
(μg/kg) (L/kg) (L/kg) (L/hr•kg) (hr) (ng•hr/mL) AUC/D
96 1.2 (0.3) 6.0 (2.3) 2.1 (0.5) 1.83˚ 40.7 (13.4) 0.50 (0.16)
†
dose in μg dexmedetomidine•HCl per kg
Units were as follows: AUC/D (ng•hr/mL per μg/kg); ˚ harmonic mean
Conclusions: The pharmacokinetics of dexmedetomidine following a 96 μg/kg bolus

intravenous dose in rabbit were characterized by a low degree of animal to animal
variability. Plasma concentration time profiles, fit to a biexponential disposition model, were
characterized by an initial apparent volume of distribution (Vc) of 1.2 L/kg, a terminal-phase
distribution volume (β) of 6.0 L/kg and a terminal elimination half-life of 1.8 hours. The
plasma clearance values in the four rabbits averaged 2.1 L/hr•kg.
5.3.11.5 Mayer MD, Machinist JM. Abbott-85499 Drug Metabolism Report No. 6 -
Metabolism and Excretion of [3H]Dexmedetomidine (Abbott-85499) in
Rats (Protocol V95-031). Abbott Laboratories Division 46 Report No.
R&D/96/233, March 1996.
The metabolism and disposition of [3H]dexmedetomidine were studied in fasted Sprague-

Dawley rats following a single intravenous or subcutaneous 0.02 mg/kg dose of the
radiolabeled drug. Less than 1% of the tritium label was converted to tritiated water in the
animal body. However, the amount of plasma tritiated water slowly increased with time and
up to 90% of total plasma radioactivity consisted of tritiated water after 72 hours. All plasma
data were appropriately corrected.
The subcutaneously administered [3H]dexmedetomidine dose appeared to be rapidly

absorbed in rats of both sexes. Significant levels of plasma radioactivity were found 0.25
hours after administration (2.5-2.7 ng Eq/mL) and remained reasonably constant for up to 6
hours. Thereafter, radioactivity levels declined slowly, reaching values of 0.04 and 0.01 ng
Eq/mL at 48 and 72 hours. The AUC0-72 for total plasma radioactivity in females
(42.29/69.13 ng Eq•h/mL; sc/iv) was about 2-fold greater than that in males (26.07/31.36 ng
Eq•h/mL; sc/iv).
The radioactive dose was excreted into both the urine and feces 72 hours following
intravenous or subcutaneous drug administration, but urinaiy excretion appeared to be
slightly greater in female rats. After an intravenous dose, urinary excretion (including
cagewash) accounted for 72.08% of the dose in females and 57.27% in males; fecal
excretion represented 26.47 and 40.99% of the dose, respectively. Following subcutaneous
administration, about 59% of the dose was recovered in the urine (including cagewash) of
females and 41.35% in males. Fecal excretion comprised 36.62% of the subcutaneous dose
in females and 60.19% in males. Total recoveries over the 3-day study period ranged from
95 to 102%. No data on the contribution of biliary excretion are presently available.
Following subcutaneous administration, peak levels of parent drug were observed at 0.5
hours (2.70 ng Eq/niL in males/2.1 ng Eq/mL in females) and declined rapidly over the next
6 hours. Exposure to parent drug in males after intravenous and subcutaneous doses was
about 8 and 20% of the AUC for total plasma radioactivity, respectively.
These values were somewhat lower in females, representing 5% (intravenous) and 11%
(subcutaneous) of the plasma total radioactivity AUC.
Plasma profiles exhibited several metabolites common to both sexes. These included the
carboxy metabolite (COOH), the hydroxy metabolite (OH), its corresponding glucuronide
(G-OH) and sulfate (SO3-OH) conjugates, as well as unidentified compounds (M-2, M-5, M-
6, M-7 and M-8). The M-6 metabolite was the major circulating metabolite in both male and
female plasma, accounting for about 21-27% of the AUC for total plasma radioactivity.
Apparent sex-related differences were noted in plasma levels of the COOH and SO3-OH
metabolites. The COOH metabolite comprised about 10-16% of the total plasma 3H AUC in
males, but represented only 2-5% of the AUC in females.
Conversely, the SO3-OH conjugate accounted for 13-18% of the total 3H AUC in female rat
plasma, while lesser amounts (0-2%) were found in male plasma.
[3H]Dexmedetomidine was extensively metabolized by rats of both sexes since less than 1%
of the dose was excreted in the urine as parent drug. Major urinary metabolites included the
COOH, OH, G-OH, SO3-OH, M-2 and M-5. The unidentified M-6, M-7 and M-8 plasma
metabolites were not found in urine. As noted previously in plasma, levels of the SO3-OH
metabolite were greater in female urine (10.99 to 17.07% of the dose) than in male urine
(0.94 to 1.19%). In addition, another sex-related metabolite tentatively identified as the
mercapturic acid conjugate of the OH metabolite was found predominantly in female rat
urine (4.84 to 6.62% of the dose). This metabolite was also noted in male rat urine but the
concentrations were considerably less (0.06 to 0.51% of the dose). The M-OH metabolite is
probably formed by conjugation of the OH or possibly the SO3-OH metabolites with
glutathione, followed by further metabolism to the mercapturic acid conjugate. Fecal patterns
generally resembled those found in urine, although possible further metabolism of the
metabolites by intestinal microflora makes interpretation difficult.
In general, the metabolism of [3H]dexmedetomidine in rats is similar to that reported for the
racemic [3H]medetomidine and a closely related analog, [3H]detomidine, in the same species.
5.3.11.6 Salonen JS. (October 1988), Orion-Farmos Study Report BA-88-04 -

Pharmacokinetics of 3H-Labelled Dexmedetomidine in the Rat
The pharmacokinetics of dexmedetomidine was studied after a single subcutaneous dose (40
µg kg-1) to rats. Tritium labeled drug was used as a tracer in the analysis.
Absorption occurred with a half-life of 6.8 minutes. The total activity excreted in the urine as
well as the activities measured in some tissues indicated that dexmedetomidine was well
absorbed. A mean maximum concentration of 10.2 ng equivalents mL-1 was observed at 20
minutes after dosing. Distribution was rapid. Its half-life was 0.25 h. The apparent volume of
distribution was 3.8 L kg-1. Most tissues seemed to be equilibrated with the drug within 20
minutes of the administration. Peak concentrations in brains (at 20 minutes) were six times
the corresponding drug level in plasma.
Elimination of unchanged dexmedetomidine from plasma had a t1/2 of 1.4 h. Elimination

from the tissues occurred rapidly with the exception of the adrenals where the half-life was
much longer. The total clearance, 61 mL min-1 kg-1, was high. Its major component was
metabolic, since only traces of the parent drug were present in urine.
Also the rapid decrease of the extractable fraction of plasma radioactivity indicated effective
biotransformation. Decrease of total radioactivity was much slower.
Excretion of radioactivity amounted to 33.9% of the dose in 24 h and to 45% in three days.
Most of the activity was excreted in the urine but a considerable fraction was also found in
feces. About 10% of the activity in urine was extractable into dichloromethane. Enzyme
hydrolysis increased this portion indicating the presence of glucuronide or sulphate
conjugates. TLC of urine extracts suggested two extractable metabolites.
Metabolism and Disposition of [3H]Abbott-85499.1 (Dexmedetomidine-
HCl) Following Subcutaneous and Intravenous Administration to Dogs
(Protocol V96-020).Abbott Laboratories Division 46 Report No.
R&D/97/291, May 1997.
The metabolism and disposition of [3H]dexmedetomidine hydrochloride were studied in

fasted beagle dogs following a single intravenous or subcutaneous 0.02 mg salt/kg dose of
the radiolabeled drug. Less than 1% of the tritium label was converted to tritiated water in
the animal body. However, the amount of plasma tritiated water slowly increased with time
and up to 74% of total plasma radioactivity consisted of tritiated water after 120 hours. All
plasma data were appropriately corrected.
Mean peak levels of radioactivity were found within 6 hours after a subcutaneous dose in
males and females (8.98 ng Eq/mL). Thereafter, radioactivity levels declined slowly,
reaching values of 0.39, 0.10 and 0.04 ng Eq/mL at 24, 48 and 120 hours. Comparison of the
AUC0-120 for total plasma radioactivity after subcutaneous administration (110.38 ng
Eq•h/mL) with that after an intravenous dose (101.81 ng Eq•h/mL) indicated excellent
absorption.
The radioactive dose was excreted primarily into the urine following intravenous or
subcutaneous drug administration. Sex-related differences in excretion were not apparent.
After an intravenous dose, urinary excretion (including cagewash) accounted for a mean of
81.57% while fecal excretion represented 13.35% of the dose. Following subcutaneous
administration, 83.11% of the dose was found in the urine (including cagewash) and 12.94%
was recovered in the feces. Average total recoveries over the 5-day study period ranged from
about 92 to 98%.
Following subcutaneous administration, peak plasma levels of parent drug (4.39 ng Eq/mL)
in males and females were observed at 2 hours and declined slowly over the next 12 hours.
The AUC for dexmedetomidine after a subcutaneous (19.03 ng Eq•h/mL) and intravenous
(15.14 ng Eq•h/mL) dose indicated excellent bioavailability. Exposure to parent drug after
both doses represented about 21 to 25% of the AUC for total plasma radioactivity. Plasma
metabolites common to both sexes included the carboxy metabolite (COOH), the hydroxy
metabolite (OH), its corresponding glucuronide (G-OH) and sulfate (SO3-OH) conjugates,
which represented about 5 to 12% of the AUC for total plasma radioactivity. Unidentified
metabolites accounted for about 50% of the AUC for total plasma radioactivity.
[3H]Dexmedetomidine HCl was extensively metabolized by dogs of both sexes since less
than 1% of the dose was excreted in the urine as parent drug. Metabolites tentatively
identified in the urine include COOH, OH, G-OH and SO3-OH. These metabolites
individually accounted for about 2-12% and collectively accounted for 38% of the total dose
recovered in urine. Unidentified compounds collectively comprised 42% of the dose in urine.
Fecal patterns generally resembled those found in urine, except that G-OH was not detected.
The major fecal metabolite (D-5), which accounted for 2.48% of the dose, has not been
identified.
In general, the metabolism of [3H]dexmedetomidine in beagle dogs is similar to that reported

previously for Sprague Dawley rats.
Phase I Study of the Metabolism and Excretion of
[3H]Dexmedetomidine•HCl (Abbott-85499.1) in Normal Male Subjects
(Protocol Dex-96-018). Abbott Laboratories Division 46 Report No.
R&D/97/457, September 1997.
The metabolism and excretion of [3H]dexmedetomidine HCl were studied in 5 healthy adult
male subjects following a 10 minute 2 µg/kg intravenous infusion of the radiolabeled drug.
Blood, urine and feces were collected during a 9 day period following drug administration;
an additional blood sample was obtained on Day 23 or 24. Total radioactivity levels and
metabolic patterns were determined in plasma and excreta samples. All values are expressed
as ng equivalents of the free base.
The pattern of total plasma radioactivity was remarkably similar in all subjects. The
concentrations decreased from a peak mean value of 3.18 ng Eq/g at 10 minutes to 1.51 ng
Eq/g at 30 minutes. After 30 minutes, the levels rose again to reach a peak mean
concentration of 2.02 ng Eq/g at 2 hours, primarily due to the appearance of parent drug N-
glucuronides (G-Dex-1 and G-Dex-2) in the plasma. A much smaller increase was noted at
about five hours, possibly indicating enterohepatic cycling. Thereafter, the levels of plasma
radioactivity declined gradually over a period of nine days and traces were still present up to
24 days. Including a 23/24-day time point, the mean half-life for total plasma tritium was
estimated to be 10.75 days, which is comparable to that of tritiated water in man (9.46 days).
Analysis of whole blood samples from 0.25 to 12 hours after dosing indicated virtually no
penetration of radioactivity into the cellular fraction.
An average of 95.17% of the radioactive dose was excreted in the urine, whereas 4.08% was
recovered in the feces after 9 days. A mean of ca. 85% of the dose in urine was recovered
within 24 hours. Total recoveries were excellent, ranging from 98.62 to 101% (average
99.25%).
The mean Cmax of dexmedetomidine (3.11 ng/g) was reached at the end of the 10 minute
infusion period and declined rapidly with an estimated mean terminal elimination half-life of
about 3 hours. The AUC0-24 for unchanged parent drug ranged from 2.72 to 4.30 ng•h/g
(average 3.26 ng•h/g). Comparison of the AUC0-24 for dexmedetomidine with that of total
plasma radioactivity over the same time course indicated that unchanged parent drug
accounted for an average of 14.70% of the plasma total radioactivity. N-glucuronides of
dexmedetomidine were the major circulating metabolites. G-Dex-1 (35.19%) and G-Dex-2
(6.17%) together accounted for 41.37% of the AUC0-24 for total plasma radioactivity. The H-
1 and H-3 metabolites were also major plasma components, accounting for 20.55% and
10.45% of the AUC0-24 for total radioactivity. Other minor metabolites include the carboxy
(COOH), N-methylated (N-Meth) and the glucuronide conjugate of hydroxylated
dexmedetomidine (G-OH), individually representing 0.29% to 3.02% of the AUC0-24 for
plasma total radioactivity. Additional unidentified minor metabolites collectively account for
the remaining 5.78% of total AUC.
Unchanged dexmedetomidine was not detected in the urine, suggesting extensive

metabolism. Major urinary metabolites were G-Dex-1 and G-Dex-2, which together
represented an average of about 34% of the dose. The H-1 metabolite accounted for an
average of 14.51% of the dose, while the COOH, OH and G-OH metabolites individually
comprised 1.11 to 7.66% of the dose. The H-3 metabolite was not found in the urine.
Approximately 32% of the dose excreted into the urine consisted of unidentified polar
metabolites. Fecal patterns generally resembled those found in urine.
The data indicate that a 2 µg/kg dose of [3H]dexmedetomidine-HCl given intravenously to

normal human subjects undergoes extensive metabolism by Phase I and Phase II pathways
and is excreted predominantly into the urine.
5.3.11.9 Kukulka MJ, Machinist JM. Abbott-85499 Drug Metabolism Report No. 8 -
In Vitro Protein Binding of [3H] Abbott-85499 (Dexmedetomidine) in
Mouse, Rat, Dog, Monkey and Human Plasma (Protocol V96-004). Abbott
Laboratories Division 46 Report No. R&D/96/320, July 1996.
The in vitro protein binding of [3H] Abbott-85499 (Dexmedetomidine) was determined with
an ultrafiltration technique in mouse, rat, dog, monkey and human plasma at drug
concentrations of 0.85, 8.5, 21.25, 42.5, and 85 ng base/mL. The drug was extensively bound
in the plasma of all five species and binding did not vary significantly with drug
concentration. The plasma protein binding averaged 94.89% in mice, 88.16% in rats, 92.58%
in dogs, 84.59% in monkeys, and 93.72% in humans. The binding in males and females was
similar, indicating no obvious sex-related differences in any of the species. Tritiated water
content in the plasma samples was minimal, indicating that tritium exchange had no effect on
the binding results.
5.3.11.10 Kukulka MJ, Machinist JM. Abbott-85499 Drug Metabolism Report No. 20
- In Vitro Binding of [3H] Abbott-85499 (Dexmedetomidine) to Human
Serum Albumin and α1-Acid Glycoprotein (Protocol 96-011). Abbott
Laboratories Division 46 Report No. R&D/97/338, June 1997.
The in vitro binding of [3H] Abbott-85499.1 to human serum albumin and α1-acid
glycoprotein was determined using an ultrafiltration technique. The binding of [3H] Abbott-
85499.1 to human serum albumin (40 mg/mL) averaged 80.75% and was concentration
independent from 1 to 100 ng/mL. In contrast, the binding of [3H]Abbott-85499.1 to α1-acid
glycoprotein (0.8 mg/mL) was considerably lower, averaging 63.96% bound at Abbott-
85499.1 concentrations from 1-100 ng/mL.
The importance of serum albumin as a binding protein of Abbott-85499.1 was substantiated

by showing that the binding of [3H] Abbott-85499.1 in solutions containing one-half the
normal physiological concentration of serum albumin (20 mg/mL) and either diminished,
normal, or elevated levels of α1-acid glycoprotein (0.4,0.8, or 1.6 mg/mL) was minimally
lower (70.80,75.00, and 79.12% bound, respectively) than the binding of [3H]Abbott-
85499.1 (82.22%) in a solution containing normal levels of serum albumin and α1-acid
glycoprotein (40 and 0.8 mg/mL, respectively). The protein binding of [3H]Abbott-85499.1
in a solution containing only diminished levels of albumin (20 mg/mL) was 69.40%,
suggesting that the α1-acid glycoprotein fraction does have a slight additive effect on the
total percentage of bound drug. Additional experiments in solutions containing the normal
physiological concentration of albumin (40 mg/mL) and either diminished or elevated levels
of α1-acid glycoprotein (0.4 or 1.6 mg/mL) showed that aberrant α1-acid glycoprotein
concentrations alone have little effect on the binding of [3H] Abbott-85499.1, with mean
binding values (81.63 and 85.09%, respectively) slightly different than that found in the
solution containing normal levels of both plasma proteins (82.22%).
The results from this study suggest that the unbound fraction of Abbott-85499.1 in human
plasma may be slightly higher in patients with disease states that result in substantially lower
than normal levels of serum albumin. Depending on the disease state involved, this increase
in the unbound fraction could be offset if it was accompanied by an increase in the serum
concentration of α1-acid glycoprotein, and conversely, could be enhanced if it was
accompanied by a decrease in the α1 -acid glycoprotein serum concentration.
5.3.11.11 Machinist JM. Abbott-85499 Drug Metabolism Report No.29 - Protein

Binding Interactions Between Abbott-85499-3H (Dexmedetomidine) and
Selected Other Drugs in Human Plasma (Protocol V97-034). Abbott
Laboratories Division 46 Report No. R&D/97/525, September 1997.
The effect of fentanyl, ketorolac, theophylline, digoxin and lidocaine on the in vitro protein
binding of Abbott-85499-3H in human plasma was determined using an ultrafiltration
technique. The addition of each of the drugs had little effect on the protein binding of
Abbott-85499-3H. The binding of Abbott-85499-3H in the absence of a potential displacer
was 92.71%, while the binding in the presence of the potential displacer drugs averaged
91.79 to 92.61%. Degradation of parent drug was not observed under these conditions. The
negligible changes in the plasma protein binding of Abbott-85499-3H suggest that these
medications are unlikely to cause clinically significant changes in the plasma protein binding
of Abbott-85499.
% A-85499-3H
Compound Concentration Bound
Control* 0.6 ng/mL 92.71
+ Fentanyl 3.0 ng/mL 92.61
+ Ketorolac 3.0 µg/mL 92.50
+ Theophylline 20.0 µg/mL 92.58
+ Digoxin 3.0 µg/mL 92.66
+ Lidocaine 6.0 µg/mL 91.79
* + 50% Ethanol
5.3.11.12 Machinist JM, Johnson MK. Abbott-85499 Drug Metabolism Report No. 30
- Effect of Abbott-85499 (Dexmedetomidine) on the Protein Binding of
Selected Other Drugs in Human Plasma (Protocol V97-027). Abbott
Laboratories Division 46 Report No. R&D/97/526, September 1997.
The effect of Abbott-85499 on the in vitro protein binding of [14C]phenytoin (16 µg/mL),
[14C]warfarin (2 µg/mL), [3H]ibuprofen (10 µg/mL), [3H]propranolol (0.02 µg/mL),
[3H]theophylline (20 µg/mL) and [3H]digoxin (3 ng/mL) was determined using an
ultrafiltration technique. None of these compounds appeared to be significantly displaced by
Abbott-85499. In the presence of Abbott-85499 (0.6 ng/mL), the protein binding, expressed
as a percent of the male + female average of the control samples, ranged from 99.5% of the
control (theophylline) to 102% of the control (digoxin). These data suggest that Abbott-
85499 is unlikely to cause clinically significant changes in the plasma protein binding of
these potentially coadministered medications.
% Bound
Drug Control* + Abbott-85499#
[14C]Phenyloin 93.55 93.53
[14C]Warfarin 99.38 99.37
[3H]Ibuprofen 99.55 99.55
[3H]Propranolol 75.47 75.36
[3H]Theophylline 60.99 60.69
[3H]Digoxin 33.75 34.46
#
0.6 ng/mL
*
+ 50% Ethanol
5.3.11.13 Kukulka MJ, Machinist JM. Abbott-85499 Drug Metabolism Report No. 22
- In Vitro Determination of Human Red Cell Binding of Abbott-85499-3H
(Dexmedetomidine) (Protocol V97-026). Abbott Laboratories Division 46
Report No. R&D/97/371, September 1997.
The in vitro red blood cell binding of Abbott-85499-3H (dexmedetomidine) was determined
by incubation (1 hour at 37°C) of the drug at concentrations of 0.5 and 5.0 ng/mL in human
whole blood from four subjects. Under these conditions there was no evidence for the
metabolism or degradation of Abbott-85499-3H.
Although minor concentration-dependent differences in binding were noted, the association

of the Abbott-85499-3H with human red cells was low and no marked sex- related
differences were evident Over the concentration range studied, the fraction bound to red cells
(frbc) averaged 0.183, the red blood cell to plasma concentration ratio (Crbc/Cp) 0.325, and the
whole blood to plasma concentration ratio (Cbl00d/Cp) 0.723, for both sexes.
Parameter Male Female Mean

frbc 0.180 0.186 0.183
Crbc/Cp 0.302 0.348 0.325
Cblood/Cp 0.704 0.742 0.723
5.3.11.14 Machinist JM. Abbott-85499 Drug Metabolism Report No.17 - Tissue

Distribution of Radioactivity in Rats following a Single Intravenous 0.02
mg/kg Dose of [3H]Dexmedetomidine-HCl (Abbott-85499.1). Abbott
Laboratories Division 46 Report No. R&D/96/720, January 1997.
The distribution of radioactivity in tissues and plasma of male and female Sprague Dawley
rats and male Long Evans rats was determined following a single intravenous 0.02 mg/kg
dose of [3H]dexmedetomidine-HCl (Abbott-85499.1).
In male and female Sprague Dawley rats, [3H]dexmedetomidine-related radioactivity was

rapidly and widely distributed throughout the body. The highest mean concentrations of
radioactivity in the blood, plasma and collected tissues were observed from 0.25 to 12 hours
postdose. Tissue:plasma concentration ratios were greater than 1 on at least one collection
point for all tissues except bone. The highest mean concentrations of radioactivity in the
plasma were 3.45 ng Eq/g (0.25 hr) in males and 5.36 ng Eq/g (2 hr) in females. Tritiated
water represented less than 5% of the radioactivity in plasma from 0.25 to 6 hours postdose,
but the fraction of tritiated water increased at later times when concentrations of radioactivity
were low. Radioactivity was eliminated from the plasma with an estimated half-life of 40.3
hours in males and 25.9 hours in females. The half- life of radioactivity in plasma which had
been dried to remove tritiated water was about 16 hours in rats of both sexes.
Mean concentrations of radioactivity were highest in the liver, adrenals, lungs, kidneys,
small and large intestine (including contents), stomach (including contents) and pancreas,
with values ranging from 73.7 ng Eq/g in the large intestine to 452 ng Eq/g in the adrenals.
All other collected tissues contained less than 40 ng Eq/g at all sampling times.
The highest mean concentrations of radioactivity in the brain (ca. 27 ng Eq/g) were observed
at 0.25 hours in males and females. These levels were at least 6 times greater than
corresponding plasma concentrations. Levels of radioactivity declined with time after
reaching maximum levels in all tissues, but declined more slowly in the adrenals. Except for
the adrenals, concentrations of radioactivity in blood, plasma and collected tissues at 72
hours postdose were less than 1 ng Eq/g. At 72 hours, the adrenals contained 28.1 and 58.3
ng Eq/g in males and females, respectively.
Tissues containing the highest percentage of the administered dose in male and female
Sprague Dawley rats were muscle (15.7-25.2%), liver (33.9-42.3%) and small intestine with
contents (21.6-24.2%) at 0.5 to 4 hours after dosing. Concentrations of radioactivity
remained high in the liver at subsequent time points, and together with the small and large
intestines (including contents), accounted for the majority of the remaining dosed
radioactivity. By 72 hours, <2% of the dose was associated with any of the tissues analyzed.
(241 ng Eq/g), kidneys (183 ng Eq/g) and eyes (without lens; 108 ng Eq/g). The levels in the
pigmented eyes were about 28 times higher than those in the non-pigmented eyes of Sprague
Dawley rats (3.89 ng Eq/g), suggesting binding of radioactivity to melanin. However, levels
of radioactivity in the pigmented (7.23 ng Eq/g) and non- pigmented (6.92 ng Eq/g) skin of
male Long Evans rats were comparable.
5.3.11.15 Machinist JM. Abbott-85499 Drug Metabolism Report No. 31 - Lacteal

Excretion and Fetal Tissue Distribution of Radioactivity Following a Single
Subcutaneous Dose of [3H]Dexmedetomidine•HCl (Abbott-85499.1) in the
Rat (Study No. Covance 6161-175). Abbott Laboratories Division 46 Report
No. R&D/97/565, September 1997.
The lacteal excretion, tissue distribution, and placental transfer of radioactivity were studied
in Sprague Dawley rats following administration of a 0.015 mg/kg subcutaneous dose of
[3H]dexmedetomidine-HCl (Abbott-85499.1). The tissue distribution and placental transfer
of radioactivity were evaluated in pregnant females at about Gestation Day 18. Lacteal
excretion was measured in rats approximately 10 days postpartum.
[3H]Dexmedetomidine - related radioactivity was distributed in maternal tissues and crossed

the placenta to distribute in fetal tissues. The highest mean concentrations of radioactivity in
maternal and fetal tissues occurred at 1 hour postdose for all tissues collected, except the
maternal adrenal glands, amniotic fluid, fetal blood, and fetal kidneys which reached
maximum levels at 8 hours postdose. The highest maternal levels (ng Eq base/g) were
observed in the adrenals (275.73), lungs (187.77), kidneys (62.08), liver (61.24) and ovaries
(26.47). The highest concentrations observed in the fetus were blood (7.16), liver (5.13) and
kidneys (4.78). The concentrations of radioactivity in blood, plasma, and maternal and fetal
tissues declined with time to levels which were 0.15 to 38% of the mean peak values. At 72
hours postdose, radioactivity was not detectable in the maternal brain, maternal heart, fetal
heart and fetal kidneys.
Drug-related radioactivity was detected in the milk of dams at 0.5 hours (0.88 ng Eq base/g)
and reached a maximum mean concentration at 4 hours (1.57 ng Eq base/g). Thereafter,
levels of radioactivity in milk decreased to non-detectable levels at 72 hours. The
milk:plasma concentration ratio was less than 1 at all collection time points (0.476 to 0.865),
indicating that radioactivity did not accumulate in the milk.
5.3.11.16 Salonen JS. Tissue-Specificity of Hydroxylation and N-Methylation of

Arylalkylimidazoles. Pharmacol Toxicol 1991;69:1-4.
Hydroxylation and N-methylation of three potent α2 adrenoceptor agonists detomidine,

medetomidine and dexmedetomidine by rat brain, kidney, liver and lung were studied in
vitro. NADPH-dependent hydroxylation of the 3'-methyl group was catalyzed mainly by the
microsomal fraction of liver. Monooxygenation by the other tissues was negligible. The
hepatic monooxygenase reaction was characterized by high affinity (K m 5.5- 9.8 µM) and
low capacity (Vmax 29-66 pmol/min per mg protein). Statistically significant (P <0.05)
differences between the Km and Vmax values of medetomidine and dexmedetomidine were
observed suggesting stereoselective oxidation of the drug molecule. N-Methylation of the of
the arylalkylimidazoles occurred mainly in the cytosolic fraction of the kidney. With S-
adenosylmethionine as the methyl donor, the transferase activities in other tissues were less
than 10% of the specific activity of the renal enzyme (about 7 pmol/min. per mg protein for
medetomidine). Even the renal enzyme showed a relatively low capacity (K m 250-300 µM
and Vmax 15-33 pmol/min. per mg protein). Different tissue distributions of the
arylalkylimidazole N- methyltransferase and histamine N-methyltransferase suggest that
they are two distinct enzyme species. Based on these results, aliphatic hydroxylation is the
major (metabolic) elimination mechanism of the arylalkylimidazole drugs, and liver is the
principle eliminating organ. The importance of N-methylation is diminished by its low
capacity and probable regeneration of parent drug by demethylation.
Metabolism of [3H]Dexmedetomidine, [3H]Levomedetomidine and
[3H]Medetomidine by Precision- Cut Rat Liver Slices. Abbott Laboratories
Division 46 Report No. R&D/97/504, November 1997.
The in vitro metabolism of [3H] dexmedetomidine, [3H]levomedetomidine and

[3H]medetomidine was studied using precision-cut tissue slices prepared from fresh rat
livers.
Based on the in vitro results, dexmedetomidine is metabolized by both Phase I (oxidation)

and Phase II (conjugation) reactions. The glucuronide of 3-hydroxy dexmedetomidine (G-
OH) was the major metabolite in males, while the free 3-hydroxy (OH) and carboxy
(COOH) metabolites were also prominent. The relatively minor sulfate (SO3-OH),
glutathione (GS-OH) and mercapturate (M-OH) conjugates in males were the major
metabolites in females, suggesting a sex related difference in metabolism. Neither direct N-
glucuronidation nor N-methylation of parent drug was a significant route of metabolism in
rats of either sex. Overall, the in vitro results agreed well with previous in vivo rat
dexmedetomidine metabolism studies.
The in vitro metabolism of the inactive enantiomer, [3H]levomedetomidine, by rat liver slices
was qualitatively similar to that of [3H]dexmedetomidine. Sex related differences in
[3H]levomedetomidine metabolism, however, were not as prominent as those seen with
[3H]dexmedetomidine. In rats of both sexes, the G-OH, SO3-OH, OH and COOH metabolites
represented a significant amount of the total metabolites, whereas the GS-OH and M-OH
metabolites were only minor components. However, approximately 71% of the total
[3H]levomedetomidine metabolites remain unidentified Sex-related differences in
[3H]medetomidine metabolism were also seen in rat liver slices, but, as might be anticipated,
the metabolites formed were qualitatively similar to those detected with the individual
enantiomers.
Metabolism of [3H]Dexmedetomidine, [3H]Levomedetomidine and
[3H]Medetomidine by Precision- Cut Dog Liver Slices. Abbott Laboratories
Division 46 Report No. R&D/97/454, August 1997.
The in vitro metabolism of [3H]dexmedetomidine, [3H]levomedetomidine and

[3H]medetomidine was studied using precision-cut tissue slices prepared from fresh dog
livers.
Based on the in vitro results, N-methylation of parent drug, followed by further metabolism
of the N-methyl metabolite is a significant route of dexmedetomidine metabolism in dog
liver slices. Collectively, the tentatively identified N-methyl and N-methyl related
metabolites (N-Meth COOH, N-Meth OH, N-Meth GOH and N-Meth SO3OH) represented
about 50% of the total metabolites formed. Hydroxylated dexmedetomidine and hydroxy
related metabolites (COOH, GOH and SO3OH) together represented only about 27% of all
metabolites produced. Direct N-glucuronidation of parent drug to form G-Dex-1 and G-Dex-
2 did not appear to be a significant route of metabolism in the dog.
The metabolism of the inactive enantiomer, levomedetomidine, was qualitatively similar to

that of dexmedetomidine. The N-methyl and N-methyl related metabolites together
represented about 37% of metabolites produced. However, in this instance, direct N-
glucuronidation of levomedetomidine was a significant route of metabolism, accounting for
approximately 16% of all metabolites produced. Hydroxylated dexmedetomidine and
hydroxy related metabolites (COOH, GOH and SO3OH) collectively accounted for about 5%
of all metabolites formed. Not surprisingly, metabolic patterns from dog liver slices
incubated with racemic medetomidine consisted of a mixture of the metabolites seen in the
individual enantiomer incubates.
5.3.11.19 Salonen JS. (January 1996). Pharmacokinetics and Metabolic Profiling of

3
H-Labeled Dexmedetomidine in Healthy Male Volunteers. Metabolic
Profile of 3H-Dexmedetomidine in Human Urine. Study BA-91-04 (PBR-
910208-4), Pharma-Bio Research International. Supplement 2,
Biotransformation Report, Orion-Farmos DNO JSS95051.
A single dose of dexmedetomidine 2 µg/kg, containing 3H-dexmedetomidine as tracer, was

administered intravenously to 6 human volunteers. Metabolite profiles in each volunteer's
urine were determined using both direct HPLC and TLC of extracted samples with
radioactivity detection. Hydrolysis of conjugates was tested using treatment with β-
glucuronidase/aryl sulphatase enzyme preparation prior to the chromatographic analysis.
Urinary metabolite profiles in five of the volunteers were very similar and showed three
major metabolites. These metabolites were poorly extracted with dichloromethane under
alkaline conditions and were stable against β-glucuronidase and aryl sulphatase hydrolysis.
They did not coelute with any of the available reference compounds (two monohydroxylated
derivatives and a carboxylic acid). The reference compounds seemed to correspond to only
minor metabolites present in free or conjugated forms. In contrast, one volunteer’s urine
seemed to contain monohydroxylated dexmedetomidine and the corresponding glucuronic
acid conjugate as the major metabolites and the three unknowns as minor metabolites.
Metabolism of [3H] Dexmedetomidine, [3H]Levomedetomidine and
[3H]Medetomidine by Precision- Cut Human Liver Slices. Abbott
Laboratories Division 46 Report No. R&D/97/389, July 1997
The in vitro metabolism of [3H]dexmedetomidine, [3H]levomedetomidine and

[3H]medetomidine was studied using precision-cut tissue slices prepared from fresh human
livers.
Based on the in vitro results, direct N-glucuronidation of parent drug is a significant route of
dexmedetomidine metabolism in humans. Two dexmedetomidine glucuronides (G-Dex-1
and G-Dex-2) have been isolated and their identities tentatively established by LC/MS and
NMR analysis. Collectively, G-Dex-1 (22.39%) and G-Dex-2 (14.69%) represent 37% of the
total metabolites formed. Although G-Dex-1 is formed at a rate approximately 1.5-fold
greater than G-Dex-2, the reaction appears to be catalyzed by the same
glucuronosyltransferase(s) and the variance in the reaction rates seems to be due to
differences in Vmax. Aliphatic hydroxylation (OH, 10.81%) and N-methylation (N-methyl,
10.77%) of dexmedetomidine also appear to be important pathways. Under these conditions,
formation of the carboxy metabolite (COOH, 1.02%), the glucuronide of the hydroxy
metabolite (G-OH, 1.56%) and a compound believed to be the glucuronide of the
hydroxylated N-methyl metabolite (H-1, 1.54%) represent minor routes of metabolism.
Although ca. 37% of the metabolites have not been identified, at least part of the unknown
fraction may represent further metabolism of the N-methyl metabolite. The pattern of
metabolites generated by human liver slices is qualitatively similar to those obtained from
limited plasma and urine samples from an earlier study with [3H]dexmedetomidine in human
subjects.
The metabolism of the inactive enantiomer, [3H]levomedetomidine, was qualitatively similar

to that of dexmedetomidine. However, in this instance, direct N-glucuronidation of
levomedetomidine (G-levo) was the major route of metabolism, accounting for 71.3% of the
total metabolites produced. The COOH, OH, G-OH, N-methyl and H-1 metabolites were
also found, but the concentrations were much lower than those seen with dexmedetomidine
(0.27 to 2.52% of the total levomedetomidine metabolites formed). Approximately 21% of
the metabolites have not been identified.
As might be predicted, incubation of racemic [3H]medetomidine with human liver slices

produced all three glucuronide peaks, which have been tentatively identified as G-Dex-1, G-
Dex-2 and G-Levo on the basis of similar retention times. The three glucuronides
collectively account for 68% of the total medetomidine metabolite pool. The relative
abundance of each glucuronide (G-Levo>G-Dex-1>G-Dex-2) is comparable to that observed
with the individual isomers. The distribution of the COOH, OH, G-OH, N-methyl and H-1
metabolites was similar to that observed with levomedetomidine.
These data have shown that the metabolism of dexmedetomidine and levomedetomidine by
human liver slices is qualitatively similar. Both compounds can undergo glucuronidation to
form the corresponding N-glucuronide(s). However, while direct glucuronidation is a
significant metabolic pathway for dexmedetomidine (37% of the total metabolites), it
represents the major pathway for levomedetomidine metabolism (71% of the total
metabolites).
5.3.11.21 Hickman D, Kumar G. Abbott-85499 Drug Metabolism Report No. 36 -

Identification of Cytochrome P450 Isoforms Involved in the Oxidative
Metabolism of Dexmedetomidine (Abbott-85499) and the Effect of
Dexmedetomidine on Cytochrome P450-Mediated Monooxygenase
Activities. Abbott Laboratories Division 46 Report No. R&D/97/757,
January 1998.
In vitro studies were conducted to identify the hepatic cytochrome P450 (CYP) proteins
involved in the oxidative metabolism of [3H]dexmedetomidine in human liver microsomes
and human B-lymphoblastoid microsomes containing cDNA expressed CYP proteins.
Furthermore, current literature on the effect of dexmedetomidine on selective CYP mediated
activities has been reviewed.
[3H]Dexmedetomidine was metabolized to two main products in both human liver

microsomes and human B-lymphoblastoid microsomes in the presence of NADPH. The first
product co-eluted with the medetomidine metabolite standard MPV-1305† which
corresponds to the product of hydroxylation at the benzylmethyl position meta to the
methylene bridge. The second major product co-eluted with an unidentified metabolite
which was previously detected in human plasma and designated as H-3.6 H-3, produced by
human liver microsomes in this study, has been tentatively identified as a hydroxylation
product at the methyl position on the methylene bridge.
†
MPV-1305 is the racemic mixture of phenyl-3-hydroxymethyl-dexmedetomidine and
phenyl-3-hydroxymethyl-levomedetomidine. For the purposes of this report the term MPV-
1305 will be used to describe the product of hydroxylation of dexmedetomidine, phenyl-3-
hydroxymethyl- dexmedetomidine.
MPV-1305 H-3
Based on the results of this study, it is concluded that the hydroxylation of dexmedetomidine
to MPV-1305 and H-3 is largely mediated by CYP2A6, although other CYP forms may also
play an ancillary role. Evidence for the involvement of CYP2A6 included: 1) 8-
methoxypsoralen, a CYP2A6-selective inhibitor, inhibited (41-59%) the hydroxylation to
both products; 2) coumarin, a CYP2A6-selective substrate, inhibited (34%) the
hydroxylation to MPV-1305; 3) hydroxylation was also observed with human B-
lymphoblastoid microsomes containing cDNA-expressed CYP2A6; and 4) the hydroxylation
of dexmedetomidine was inhibited (33%) by a CYP 2A6 antibody. However, several other
cDNA-expressed CYPs were also capable of catalyzing the metabolism of dexmedetomidine
to one or both major products in vitro indicating that other CYP isoforms (e.g., CYP1A2,
CYP2E1, CYP2D6 and CYP2C19) may play a role in the hydroxylation of
dexmedetomidine. These data are consistent with studies which found dexmedetomidine to
be a broad-spectrum inhibitor of metabolic reactions catalyzed by cytochromes P450. The
IC50 or Ki values for inhibition ranged from 0.2-3.3 µM for the inhibition of 1A1 (2.7 µM),
1A2 (2.0 µM), 2C9 (0.2 µM), 2C19 (3.3 µM), 2D6 (1.3 µM), 2E1 (2.2 µM) and 3A4 (0.65
and 0.85 µM) isoforms. Although CYP2A6 appeared to be the largest single contributor to
dexmedetomidine hydroxylation in vitro in human liver microsomes, this CYP isozyme was
inhibited by dexmedetomidine with much less potency (IC50 = 70 µM). These observations
can be reconciled by the fact that the affinity of the drug for the enzyme, measured here as
IC50, is not necessarily an indication of the velocity of any metabolism. The nature of
inhibition was found to be a mixed (competitive/noncompetitive) type for the inhibition of
CYP2D6-mediated dextromethorphan O-demethylation and competitive for ketamine N-
demethylation. Optical difference spectroscopy experiments with both human liver
microsomes and CYP2D6 cDNA-expressed B-lymphoblastoid microsomes indicated that
dexmedetomidine binds to the ferric heme of cytochrome P450 to yield a typical Type II
spectrum. A similar spectrum is observed after reversible binding of other imidazole
containing compounds such as ketoconazole. Since, the plasma concentrations of
dexmedetomidine at clinically relevant doses are very low (≤ 10 ng/mL; ≤ 0.04 µM)
compared to the in vitro determined IC50 or Ki values, the possibility of an inhibitory effect
of dexmedetomidine on the metabolism of coadministered drugs in vivo in humans is highly
unlikely. In a clinical drug interaction study, dexmedetomidine did not have any effect on the
pharmacokinetics of midazolam, a CYP3A substrate. This is possibly due to very low plasma
concentrations of dexmedetomidine (0.2-0.4 ng/mL), which are several fold lower than the in
vitro-determined IC50 values for CYP3A4 inhibition (0.65-0.85 µM; 110-150 ng/mL). Since
the inhibitory potency of dexmedetomidine against other CYP isoforms is approximately the
same or less than that on CYP3A4, dexmedetomidine is not likely to inhibit the metabolism
and alter the pharmacokinetics of coadministered drugs which are metabolized by other CYP
isoforms as well.
5.3.11.22 Salonen JS, Eloranta M. Biotransformation of Medetomidine in the Rat.

Xenobiotica 1990;20:471-480.
The metabolites of a novel α2-adrenoceptor agonist, medetomidine, in rat urine after

subcutaneous administration at two dose levels (80 µg/kg or 5 mg/kg), and after incubation
with rat liver fractions, were characterized by HPLC, 1H-NMR and mass spectrometry.
Hydroxylation of a methyl substituent was the main biotransformation in vitro.
Hydroxylation occurred at a rate sufficient for high metabolic clearance. The major urinary
metabolites were the glucuronide of hydroxymedetomidine (about 35% of the urinary
metabolites) and medetomidine carboxylic acid (about 40%). Unchanged medetomidine
represented about 1% or 10% of the urinary excretion products, dependent on dose. A
metabolic pathway consisting of hydroxylation with subsequent glucuronidation, or further
oxidation to the carboxylic acid is suggested.
Conversion of [3H]Dexmedetomidine to [3H] Levomedetomidine in Male
Subjects Following a 2 µg/Kg Infusion of [3H]Dexmedetomidine•HCl.
Abbott Laboratories Division 46 Report No. R&D/97/458, August 1997.
The possible chiral inversion of dextromedetomidine to its inactive enantiomer,
levomedetomidine, was assessed by 1) measuring the concentration of unchanged
[3H]levomedetomidine in plasma and 2) determining the levels of [3H]N- levomedetomidine
glucuronide(s) (G-levo) in plasma and urine of subjects who received a 2 µg/kg infusion of
[3H]dexmedetomidine·HCl (Study No. DEX-96-018).
Unchanged [3H]levomedetomidine was not detected by chiral chromatography in any of the
plasma samples. If [3H]levomedetomidine was present, it was below the limit of detection of
the analytical method (ca. 0.02 ng/mL). Results of previous in vitro studies with human liver
slices demonstrated that [3H]levomedetomidine was rapidly converted to (G-levo),
suggesting that the latter compound(s) may be present in the biological samples in lieu of
unchanged drug. Reevaluation of previous metabolism data from study DEX-96-018 did
reveal the presence of [3H]G-levo in the plasma and urine. However, exposure to [3H]G-Ievo
was slight, accounting for an average of less than 0.5% of the AUC0-24 for total plasma
radioactivity. Similarly, the amount of [3H]G-levo in the 0-72 hour samples represented a
mean of less than 1.5% of the dose. Both findings are consistent with the possibility that, to
some extent, chiral inversion of dextro- to levomedetomidine had occurred in vivo. The fact
that traces of [3H]levomedetomidine in the dose solution of [3H]dexmedetomidine used in
study DEX-96-018 contributed to the already low levels of G-levo makes the chiral inversion
pathway even less significant in humans and of doubtful clinical relevance.
5.3.11.24 Pelkonen O, Puurunen J, Arvela P, Lammintausta R. Comparative Effects

of Medetomidine Enantiomers on In Vitro and In Vivo Microsomal Drug
Metabolism. Pharmacol Toxicol 1991;69:189-194.
The effects of dexmedetomidine, a selective α2-adrenoceptor agonist, and its levo enantiomer
(MPV-1441), on the in vitro microsomal P450-dependent drug metabolizing activities as
well as on in vivo aminopyrine elimination and hexobarbital sleeping time were studied.
Both enantiomers inhibited the oxidative metabolism of several model substrates and
testosterone in rat liver microsomal incubations. Microsomal activities derived from control
animals or rats pretreated with phenobarbital were more sensitive to inhibitory effects of
dexmedetomidine than those from rats treated with 3- methylcholanthrene. Enzyme activities
in human liver microsomes were also inhibited by dexmedetomidine. Retardation of the
elimination of the elimination of aminopyrine was dose-dependent; elimination was
marginally retarded with doses up to 100 µg/kg (from 17 to 23 min.; both enantiomers).
Higher doses of the levo-enantiomer prolonged aminopyrine half-life to 78 (1 mg/kg) and
162 min. (10 mg/kg). The hexobarbital sleeping time was prolonged by the dose of 1 mg/kg
of the levo-enantiomer (128 min. versus 20 min. in controls), while the dose of 0.1 mg/kg
had not effect (23 versus 20 min.). These studies indicate that both enantiomers of
medetomidine are inhibitors of microsomal drug metabolism in vitro, but significant effects
on aminopyrine elimination or hexobarbital sleeping time are apparent only at doses which
do not allow the use of dexmedetomidine because of excessive sedative effect.
5.3.11.25 Rodrigues AD. Abbott-85499 Drug Metabolism Report No.13- The In Vitro
Interaction of Dexmedetomidine with Human Liver Microsomal
Cytochrome P450 2D6 (CYP2D6). Abbott Laboratories Division 46 Report
No. R&D/96/557, August 1996.
The effect of dexmedetomidine (DEX; Abbott-85499) on cytochrome P450 2D6 (CYP2D6)-

dependent dextromethorphan O-demethylase (DMase) activity was studied using native
human liver microsomes in an attempt to predict DEX-drug interaction(s).
Over the concentration studied (0.01-4.0 µM), DEX inhibited human liver microsomal
DMase activity in a concentration-dependent manner, and the concentration of DEX required
to inhibit activity by 50% (IC50) was 1.3 ± 0.25 µM (mean ± SD, n = 5 livers). In this regard,
DEX was less potent than quinidine (QND), a prototypical and clinically relevant CYP2D6
inhibitor (IC50 = 0.18 ±0.02 µM; mean ± SD, n = 3 livers). Similar results were obtained with
human B-lymphoblastoid microsomes containing cDNA- expressed CYP2D6 (DEX, IC50 =
2.0 µM; QND, IC50 = 0.15 µM). Formal kinetic analyses with native human liver
microsomes revealed that DEX was a reversible mixed (competitive/noncompetitive)
inhibitor of DMase activity, where Kies > Ki and α > 1 (α = Kies/Ki). With three different
human livers, the mean (± SD) apparent Ki and Kies was 0.4 (± 0.2) µM and 2.3 (± 0.9) µM,
respectively (α = 8.1 ± 6.8). As expected, QND was a more potent inhibitor (K i = 0.07) µM,
mean of two livers) and exhibited pure competitive inhibition.
Additional studies revealed that DEX elicited a Type IIb difference spectrum (max -436 nm;
λmin -414 nm) when added to human B-lymphoblast microsomes containing cDNA-expressed
wild type CYP2D6. In this instance, binding to CYP2D6 was characterized by a spectral
dissociation constant (Ks) of 0.4 µM that was identical to the Ki obtained with native human
liver microsomes. These data indicated that DEX was able to reversibly bind to the oxidized
(ferric) heme iron of CYP2D6. It is postulated that binding occurs via the 4(5)-substituted
imidazole moiety.
Based on the results of this study, it is concluded that DEX is a relatively potent inhibitor of
CYP2D6. However, its potency is lower than that of QND (~6-fold higher Ki). Since the
inhibition of CYP2D6 is characterized by a Ki (0.4 µM) that is well above the anticipated
levels of total (free and protein-bound) DEX in plasma (≤ 10 ng/mL; ≤ 0.04 µM;
[DEX]plasma/Ki ratio ≤, 0.1), these results indicate that the interaction of the drug with
CYP2D6 is clinically irrelevant. By comparison, the plasma concentration (-1.0 µM) to in
vitro Ki (0.07 µM) ratio for QND is 14.3.
5.3.11.26 Kharasch ED, Hill HF, Eddy AC. Influence of Dexmedetomidine and
Clonidine on Human Liver Microsomal Alfentanil Metabolism.
Anesthesiology 1991;75:520-524.
Perioperative administration of the α2 agonist clonidine has been shown to increase plasma
alfentanil concentrations; however, the mechanism for this pharmacokinetic drug interaction
is unknown. Because alfentanil undergoes extensive hepatic biotransformation, clonidine
inhibition of alfentanil metabolism may alter alfentanil disposition. The first purpose of this
investigation was to test the hypothesis that clonidine impairs human liver alfentanil
metabolism. The new highly selective α2 agonist dexmedetomidine (D-medetomidine) is a
substituted imidazole and thus may inhibit hepatic drug biotransformation. The second
purpose of this study, therefore, was to assess the effect of D-medetomidine and its levo (L)
isomer on alfentanil biotransformation. Human liver microsomal alfentanil metabolism was
assessed in vitro using a gas chromatography-mass spectrometry assay. Clonidine, as
concentrations as great as 10 µM (far exceeding therapeutic levels), had no significant effect
on alfentanil oxidation. In contrast, D-medetomidine and its optical isomer L-medetomidine
were potent inhibitors of human liver microsomal alfentanil metabolism. The concentration
producing 50% inhibition (IC50) of alfentanil (10 µM) oxidation was 0.7-1.0 and 2.8-4.0 µM
for D-medetomidine and L-medetomidine, respectively. Preincubation of D-medetomidine
with microsomes did not enhance the inhibition of alfentanil metabolism. These results
suggest that the increased alfentanil plasma concentrations and potentiation of alfentanil
anesthesia associated with clonidine do not result from clonidine inhibition of alfentanil
metabolism. D-Medetomidine impairment of alfentanil metabolism, however, if present at
therapeutic concentrations, may influence alfentanil disposition.
5.3.11.27 Kharasch ED, Herrmann S, Labroo R. Ketamine as a Probe for

Medetomidine Stereoisomer Inhibition of Human Liver Microsomal Drug
Metabolism. Anesthesiology 1992;77:1208-1214.
Medetomidine (MED) is a novel, selective (α2-adrenergic agonist with potent sedative,

hydnotic and analgesic properties, currently undergoing evaluation as an anesthetic adjuvant.
The pharmacological effects of MED are stereospecific, due entirely to the D-isomer
(DMED), whereas the L-isomer (LMED) is essentially inactive. DMD, a 4 (5) substituted
imidazole, has been shown to inhibit adrenal steroidogenesis and human liver microsomal
alfentanil metabolism, reactions mediated by cytochrome P450. The mechanism of MED
inhibition of cytochrome P450 is unknown. The purpose of this investigation was to
determine the mechanism of DMED inhibition of human cytochrome P450-mediated
microsomal metabolism, using ketamine as a probe. Ketamine undergoes extensive hepatic
biotransformation and has been used previously to characterize the effects of imidazole
anesthetics on human P45-catalyzed drug metabolism. Ketamine N-demethylation by
microsomes from three human livers was measured by gas chromatography-mass
spectrometry with selected ion monitoring. DMED was a potent competitive inhibitor of
S(+) ketamine N-demethylation with a Ki of 0.11-0.18 µM for the high affinity ketamine
demethylase. The IC50 for DMED inhibition of therapeutic concentrations of racemic
ketamine (10 µM) was 0.15 ± 0.02 µM. Preincubation of DMED with microsomes and a
NADPH generating system prior to ketamine addition had not additional effect on the
inhibition of ketamine demethylase activity, thereby implicating the parent compound rather
than a DMED metabolite as the inhibitory species. LMED, although pharmacologically
inactive, had a greater inhibitory effect than DMED on racemic ketamine and ketamine
enantiomer demethylation at therapeutic concentrations. Spectral studies showed that DMED
interacted with microsomal cytochrome P450 to elicit a Type II binding spectrum. These
results illustrate that DMED is a potent inhibitor of cytochrome P450 catalytic activity,
inhibiting ketamine demethylation by direct binding to P450 heme iron and competitive
inhibition at the substrate binding site, DMED, compared to the mixture of isomers, has a
lesser potential for drug interactions at equally effective concentrations.
5.3.11.28 Virtanen R. Orion-Pharma Research Report - The Effects of

Dexmedetomidine N-Glucuronides on Alpha-2 Adrenoceptors In Vitro and
In Vivo. Study No. CNS97122100010, August 1997.
Two isomeric dexmedetomidine N-glucuronide metabolites (G-DEX-1 and G-DEX-2) were

tested for alpha-2 adrenoceptor agonist activity in vitro (electrically stimulated rat vas
deferens and guinea pig ileum preparations) and in vivo (peripherally mediated
cardiovascular effects in the pithed rats and centrally mediated mydriasis response in
anesthetized rats). Both G-DEX-1 and G-DEX-2 behaved as presynaptic alpha-2
adrenoceptor agonists in vitro in the vas deferens and guinea pig ileum assays but they were
1-2 orders of magnitude times less potent than the parent compound. No central or peripheral
alpha-2 agonist activity could, however, be seen in vivo with either of the metabolites when
tested up to doses of 0.3-0.4 mg/kg iv whereas dexmedetomidine showed the typical alpha-2
adrenoceptor mediated effects already at doses of 1-3 µg/kg iv and above.
5.3.11.29 Aantaa R, Kallio A, Virtanen R. Dexmedetomidine, a Novel α2-Adrenergic

Agonist. A Review of its Pharmacodynamic Characteristics. Drugs of the
Future. 1993; 18(l):49-56.
A vast number of clinical studies over two decades have indicated that the α2- adrenoceptor
agonists (α2-agonists) have several beneficial effects as adjuncts to anesthesia and surgery.
These studies have demonstrated, among other effects, reduced anesthetic requirements and
improved cardiovascular and adrenergic stability during surgery. The prospect of potent
analgesic activity after intrathecal and epidural application of α2-adrenoceptor agonists adds
to the attractiveness of this class of drugs. The greater relative potency as well as higher
selectivity and specificity of dexmedetomidine [(+)-(S)-4-[l-(2, 3-dimethylphenyl)ethyl]1H-
imidazole] compared to clonidine, the antihypertensive and archetype of α2-agonists, has
raised great expectations with regard to the usefulness of this drug in adjunct to anesthesia.
α2-Agonists are widely used in veterinary anesthesia and the racemic mixture medetomidine
(DomitorR), which includes dexmedetomidine and the pharmacologically inactive l-
enantiomer (levomedetomidine), has been approved for veterinary anesthesia in several
countries.
Metabolism and Excretion of [3H]Dexmedetomidine Following Intravenous
or Subcutaneous Administration to Chronically Bile Duct Cannulated Rats
R&D/96/443, July 1996.
The biliary excretion of [3H]dexmedetomidine (Abbott-85449) was studied in male and

female Hilltop Sprague-Dawley chronically bile duct cannulated rats following intravenous
and subcutaneous administration of a single 0.02 mg/kg dose of the hydrochloride salt.
Radioactivity was excreted into the bile of male and female rats. An average of 51.58 and
45.37% of the radioactive dose was recovered in rat bile 24 hours after intravenous and
subcutaneous administration, respectively, indicating that biliary secretion was a significant
excretory route in this species. Urinary (including cagewash) excretion accounted for
41.35% (intravenous) and 36.73% (subcutaneous) of the dose after 24 hours. Total
recoveries ranged from 83.15% to 96.62%.
Dexmedetomidine was extensively metabolized since unchanged parent drug represented 0

to 0.1% of the dose in bile after either route of administration. The major biliary metabolites
in rats of both sexes were the glucuronide of a hydroxylated metabolite (G-OH) and an
unidentified conjugate, M-2. Levels of G-OH represented 14.0 to 15.91% of the dose after
intravenous administration and 12.34 to 18.17% after a subcutaneous dose. Concentrations
of M-2 ranged from 5.61 to 9.88% of the dose after intravenous and subcutaneous doses.
Biliary concentrations of the carboxy metabolite (COOH) and a mercapturic acid conjugate
(M-OH) were low, averaging 0 to 1.27% of the dose. Levels of a sulfate (SO3-OH) and a
glutathione (GS-OH) conjugate were each 3-to 6-fold higher in female rat bile. The SO3-OH
conjugate represented 1.31 and 0.85% of the dose in males and 3.97 and 2.68% of the dose
in females after intravenous and subcutaneous doses, respectively. The GS-OH metabolite
accounted for about 1% of the dose in males and 5.36 to 6.46% of the dose in females after
both routes of administration. Unidentified metabolites represented 12 to 18% of the dose.
Urinary metabolites were qualitatively similar to those seen in bile, with unchanged parent
drug accounting for about 0.4 to 1.1% of the dose. Major metabolites in males included
COOH, OH, G-OH and unidentified components M-2 and M-5 (1.95 to 7.12% of the dose).
The same metabolites were found in females at somewhat lower values (1.5 to 3.26% of the
dose). Only traces (ca. 0.1%) of the GS-OH conjugate were found in urine from either sex.
Urinary levels of the SO3-OH and M-OH conjugates were about 10- and 4- fold higher in
females, respectively. In females, the SO3-OH conjugate represented 7.23 (intravenous) and
4.18% (subcutaneous) of the dose, while in males this metabolite accounted for 0.41 to
0.75% of the dose after either route of administration. Similarly, the M-OH conjugate
accounted for 1.25 to 1.7% of the dose in females and 0 to 0.33% of the dose in males.
5.3.11.31 Schwietert HR, Leeuwenkamp OR, van Lier JJ, Mensink CK, Sollie FAE,
Jonkman JHG. Pharmacokinetics and Metabolic Profiling of 3H-Labeled
Dexmedetomidine in Healthy Male Volunteers. Biometrical Report. Study
BA-91-04 (PBR-910208-4), Pharma-Bio Research International B.V.,
March 1994.
The purpose of this study was to determine the disposition and routes of elimination of
dexmedetomidine and its putative metabolites after intravenous administration. In an open
label, single dose study, six healthy male volunteers received an intravenous infusion of 2.0
µg/kg (tritium-labeled) dexmedetomidine hydrochloride for five minutes. The participants
were hospitalized from the evening before until 240 h after 3H-dexmedetomidine
administration. All urine and feces were quantitatively collected during hospitalization.
Blood samples were serially obtained according to an appropriate schedule up to 240 h after
drug administration. Safety assessments (blood pressure, heart rate, body temperature and
12-lead ECG) were made at regular intervals. In addition, an ECG was continuously
recorded by telemetric monitoring for at least six hours following drug administration. Total
3
H-radioactivity was measured in plasma, urine and feces samples. Concentration data as
derived from total radioactivity measurement were subjected to pharmacokinetic and
descriptive statistical analysis. Results on metabolic profiling will be provided separately by
the Sponsor as an addendum to this report. The table below summarizes the key
pharmacokinetic parameters as derived from total plasma, urine and feces radioactivity
versus time measurements after single dose intravenous administration of tritium-labeled
dexmedetomidine to sex subjects. The results indicated a slow but virtually complete
elimination of total plasma 3H-radioactivity after a single dose intravenous administration of
tritium-labeled dexmedetomidine. Since it was estimated from a previous pharmacokinetic
study in healthy volunteers, that the half-life of the parent compound is approximately 2.3 h,
it is highly probable that the slow elimination rate of the total plasma 3H-radioactivity in (his
study is due to the extensive formation of one or more metabolites with (a) long elimination
half-life/lives. These/this putative metabolite(s) are mainly cleared by the renal route as
evidenced by the major percentage of the intravenous dose excreted in urine and the small
remainder recovered from feces.
Dexmedetomidine
Actual Dose Urine Feces Toral
Administered tl/2 Varea Recovery Recovery Recovery
(nmol) (h) AUC0- Cl (L/Kg) (%) (%) (%)
Mean* 566.2 189 210.3 0.038 10.41 88.84 5.86 94.7
SD 37.3 20 36.2 0.005 1.93 5.42 1.44 4.25

AUC0- = nmol Eq•h/L.; Cl = L/h•kg •n = 6
Since dexmedetomidine is a potent and selective centrally active α2-agonist with mild to
moderate sedative/anesthetic effects, all volunteers fell asleep soon after the end of the five-
minute infusion. The mean sleep duration after the infusion was approximately 1.5 hours.
The medication was well tolerated by the participants in this study.
5.3.11.32 Thomas SB. Abbott-85499 Drug Metabolism Report No. 2 - Preparative

Separation and Analysis of the Tritiated Dextro and Levo Enantiomers of
Medetomidine. Abbott Laboratories Division 46 Report No. R&D/95/949,
March 1996.
The aim of this work was to prepare microgram quantities of the tritiated dextro and levo-
enantiomers of medetomidine of high optical purity. A published method exists for the
separation of the two enantiomers using a commercially available α1-acid glycoprotein (α1-
AGP) column operated in a reversed-phase mode with a phosphate buffer as the mobile
phase. However, the poor capacity factor of this column and the use of phosphate salt in the
method prohibited its use for preparative resolution of the enantiomers. Therefore, a direct,
fast and reproducible separation method using a commercially available chiral stationary
phase (CSP) composed of cellulose tris (3,5-dimethylphenyl- carbamate) chemically bonded
to 3-aminopropyl silica gel, Chiralcel OD, and a mobile phase consisting of n-hexane, 2-
propanol and trifluoroacetic acid was developed and used.
About 4.78 mCi of dextro isomer (D-isomer) and 4.92 mCi of levo isomer (L-isomer) were
obtained. They were shown to have a specific activity of 76.0 Ci/mmol and 84.1 Ci/mmol,
respectively, with radiochemical purities of >96% and optical purities of >98%. The dextro
isomer was assigned Lot No. 50498-ST-l13 and the levo isomer was assigned Lot No.
50498-ST-111.
5.3.11.33 Hui YH. Abbott-85499 Drug Metabolism Report No. 4 - A GC-MS Method
for the Quantitation of Dexmedetomidine (Abbott-85499) in Plasma.
Abbott Laboratories Division 46 Report No. R&D/96/073, May 1996.
This report describes an analytical method for the quantitation of Dexmedetomidine (Abbott-
85499) in human plasma, using gas chromatography with mass spectrometric detection (GC-
MS). Compound d-MPV-872 All was used as the internal standard. The assay procedure
consisted of extractive derivatization of both analytes from a plasma matrix using
pentafluorobenzoyl chloride (PFB-C1) as the derivatization reagent and hexane as the
extraction solvent. Resolution of the analyte peaks was achieved using a DB-1701 (J & W,
30 m x 0.25 mm x 0.25 µ) capillary column with a carrier gas of helium. Analytes were
monitored using mass spectrometry (HP MS Engine®) with negative chemical ionization
(NCI). The chromatographic run time was about 9.3 minutes.
The standard curves derived from the peak area ratio (analyte/internal standard) versus
concentration of Abbott-85499 in human plasma were linear over the range of approximately
10 - 1500 pg/mL, with correlation coefficients ranging from 0.992 - 0.998. The Y-intercepts
were not significantly different from zero. The lowest standard level at 10 pg/mL had an
inter-day accuracy of 97.7% with a CV of 9.5% for nine measurements, indicating that this
concentration could be used as the lower limit of quantitation (LOQ).
The intra-assay accuracy for Abbott-85499 in human plasma was excellent The mean of
three replicates for the four QC levels derived from the three day validation ranged from
102.1 to 116.7% of the theoretical concentration, with CVs ranging from 0.7 -16.6%. The
inter-assay accuracy and precision were also good. Mean assay results for the three different
days of analysis were 114.7, 110.8, 111.8 and 105.9% of the theoretical concentrations for
the four QC levels of 10.5, 52.5, 839.1 and 1573.4 pg/mL, respectively. The corresponding
inter-assay CVs were 3.2, 6.8, 6.3 and 8.5%. The method was also validated in dog plasma.
Similar performance was obtained in this matrix. There were no anomalies affecting
precision or accuracy that could be assigned to the matrix. Intra-assay mean accuracy for
triplicate QCs in dog plasma ranged from 87.7 - 106.9%, with CVs between 1.7 - 7.3%.
The stability of Abbott-85499 in dog plasma was also examined. The results indicated that
Abbott-85499 was stable in dog plasma when stored at -20°C for more than one month.
Longer term (6 months and one year) stability studies are in progress. Abbott-85499 was also
stable when subjected to three cycles of freezing and thawing. Abbott-85499 was stable in
plasma stored at room temperature for at least 8.5 hours.The pentafluoroyl benzoyl
derivatives of Abbott-85499 and the internal standard were stable in the reconstitution
solution when stored in a refrigerated autosampler tray for up to 57 hours.
5.3.12 References
1. Hui YH. Abbott-85499 Drug Metabolism Report No. 34 - Plasma concentrations of

dexmedetomidine following subcutaneous dosing in rat (Protocol V96-557). Abbott

dexmedetomidine following a single IV or IM dose in dog (Protocol V96-556). Abbott
3. Hui YH, Marsh KC. Abbott-85499 Drug Metabolism Report No. 5 - Plasma
concentrations of Abbott-85499 (dexmedetomidine) following repeat intrathecal
administration in dog (Protocol TB85-224). Abbott Laboratories Division 46 Report
No. R&D/96/074, April 1996.

dexmedetomidine following intravenous dosing in rabbit (Protocol V96-558). Abbott
5. Mayer MD, Machinist JM. Abbott-85499 Drug Metabolism Report No. 6 -

Metabolism and excretion of [3H]dexmedetomidine (Abbott-85499) in rats (Protocol
V95-031). Abbott Laboratories Division 46 Report No. R&D/96/233, March 1996.
6. Salonen JS. (October 1988). Orion-Farmos Study Report - Pharmacokinetics of 3H-

labelled dexmedetomidine in the rat. Study No. BA-88-04.

Metabolism and disposition of [3H] Abbott-85499.1 (dexmedetomidine-HCl) following
subcutaneous and intravenous administration to dogs (Protocol V96-020). Abbott
Laboratories Division 46 Report No- R&D/97/291, May 1997.
8. Mayer MD, Machinist JM. Abbott-85499 Drug Metabolism Report No. 26 - Phase I
study of the metabolism and excretion of [3H]dexmedetomidine·HCl (Abbott-85499.1)
in normal male subjects (Protocol Dex-96-018). Abbott Laboratories Division 46
Report No. R&D/97/457, December 1997.
9. Kukulka MJ, Machinist JM. Abbott-85499 Drug Metabolism Report No. 8 – In vitro
protein binding of [3H]Abbott-85499 (dexmedetomidine) in mouse, rat, dog, monkey,
and human plasma (Protocol V96-004). Abbott Laboratories Division 46 Report No.
R&D/96/320, July 1996.
10. Kukulka MJ, Machinist JM. Abbott-85499 Drug Metabolism Report No. 20- In vitro
binding of [3H] Abbott-85499 (dexmedetomidine) to human serum albumin and 1-acid
glycoprotein (Protocol V96-011). Abbott Laboratories Division 46 Abbott Laboratories

Division 46 Report No. R&D/97/338, June 1997.
11. Machinist JM. Abbott-85499 Drug Metabolism Report No. 29 - Protein binding
interactions between Abbott-85499-3H (dexmedetomidine) and selected other drugs in
human plasma (Protocol V97-034). Abbott Laboratories Division 46 Report No
12. Machinist JM, Johnson MK. Abbott-85499 Drug Metabolism Report No. 30 - Effect
of Abbott-85499 (dexmedetomidine) on the protein binding of selected other drugs in
human plasma (Protocol V97-027). Abbott Laboratories Division 46 Report No.
13. Kukulka MJ, Machinist JM. Abbott-85499 Drug Metabolism Report No. 22 - In vitro
determination of human red cell binding of Abbott-85499-3H (dexmedetomidine)
(Protocol V97-026). Abbott Laboratories Division 46 Report No. R&D/97/371,
September 1997.
14. Machinist JM. Abbott-85499 Drug Metabolism Report No. 17 - Tissue distribution of
radioactivity in rats following a single intravenous 0.02 mg/kg dose of
[3H]dexmedetomidine-HCl (Abbott-85499.1). Abbott Laboratories Division 46 Report
No. R&D/96/720, January 1997.
15. Machinist JM. Abbott-85499 Drug Metabolism Report No. 31- Lacteal excretion and
fetal tissue distribution of radioactivity following a single subcutaneous dose of
[3H]dexmedetomidine-HCl (Abbott-85499.1) in the rat (Study No. Covance 6161-175).
Abbott Laboratories Division 46 Report No. R&D/97/565, September 1997.
16. Salonen JS. Tissue specificity of hydroxylation and N-methylation of

Arylalkylimidazoles. Pharmacol Toxicol 1991;69:1-4.
Metabolism of [3H]dexmedetomidine, [3H]levomedetomidine and [3H]medetomidine by
precision-cut rat liver slices. Abbott Laboratories Division 46 Report No. R&D/97/504,
November 1997.
precision-cut dog liver slices. Abbott Laboratories Division 46 Report No.
R&D/97/454, August 1997.
19. Salonen JS. (January 1996). Pharmacokinetics and metabolic profiling of 3H- labelled
dexmedetomidine in healthy male volunteers. Metabolite profile of 3H-
dexmedetomidine in human urine. Study BA-91-04 (PBR-910208-4), Pharma Bio-
Research International, Supplement 2, Biotransformation Report, Orion-Farmos DNO

JSS95051.
precision-cut human liver slices. Abbott Laboratories Division 46 Report No.
R&D/97/389, July 1997.
21. Hickman D, Kumar GN. Abbott-85499 Drug Metabolism Report No. 36 -

Identification of cytochrome P450 isoforms involved in the oxidative metabolism of
dexmedetomidine (Abbott-85499) and the effect of dexmedetomidine on cytochrome
P450-mediated monooxygenase activities. Abbott Laboratories Division 46 Report No.
R&D/97/757, January 1998.
22. Salonen JS, Eloranta M. Biotransformation of medetomidine in the rat. Xenobiotica

1990;20:471-480.
Conversion of [3H]dexmedetomidine to [3H]levomedetomidine in male subjects
following a 2 µg/kg infusion of [3H]dexmedetomidine-HCl. Abbott Laboratories
Division 46 Report No. R&D/97/458, August 1997.
24. Pelkonen O, Puurunen J, Arvela P, Lammintausta R. Comparative effects of

medetomidine enantiomers on in vitro and in vivo microsomal drug metabolism.
Pharmacol Toxicol 1991;69:189-194.
25. Rodrigues AD. Abbott-85499 Drug Metabolism Report No. 13 - The in vitro
interaction of dexmedetomidine with human liver microsomal cytochrome P450 2D6
(CYP2D6). Abbott Laboratories Division 46 Report No. R&D/96/557, August 1996.
26. Kharasch ED, Hill HF, Eddy AC. Influence of dexmedetomidine and clonidine on
human liver microsomal alfentanil metabolism. Anesthesiology 1991;75:520-524.
27. Kharasch ED, Herrmann S, Labroo R. Ketamine as a probe for medetomidine

stereoisomer inhibition of human liver microsomal drug metabolism. Anesthesiology
1992;77:1208-1214.
28. Virtanen R. (August 1997). Orion-Pharma Research Report - The effects of

dexmedetomidine N-glucuronides on alpha-2 adrenoceptors in vitro and in vivo. Study
No. CNS97122100010.
29. Aantaa R, Kallio A, Virtanen R. Dexmedetomidine, a novel α2-adrenergic agonist. A

review of its pharmacodynamic characteristics. Drugs of the Future 1993;18:49-56.
Metabolism and excretion of [3H]dexmedetomidine following intravenous or
subcutaneous administration to chronically bile duct cannulated rats (Protocol V96-
014). Abbott Laboratories Division 46 Report No. R&D/96/443, July 1997.
31. Schwietert HR, Leeuwenkamp OR, van Lier JJ, Mensink CK, Sollie FAE,
Jonkman JHG. (March 1994). Pharmacokinetics and metabolic profiling of 3H-
Iabelled dexmedetomidine in healthy male volunteers. Biometrical report. Study BA-
91-04 (PBR-910208-4), Pharma Bio-Research International B.V.
32. Thomas SB. Abbott-85499 Drug Metabolism Report No. 2 - Preparative separation and
analysis of the tritiated dextro and levo-enantiomers of medetomidine. Abbott
Laboratories Division 46 Report No. R&D/95/949, March 1996.
33. Hui YH. Abbott-85499 Drug Metabolism Report No. 4 - A GC-MS method for the
quantitation, of dexmedetomidine (Abbott-85499) in plasma. Abbott Laboratories
Division 46 Report No. R&D/96/073, May 1996.

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Abbott-85499

Drug Metabolism Report No. 40

Overview of the Absorption, Distribution, Metabolism and

[Signature: Illegible] 03-12-98

Paulette Johnson, B.S., Samuel B. Thomas, M.S., Dean Hickman, Ph.D.,

Peer Reviewed by:

[Signature: Illegible] 03-12-98

Approved and Submitted by:

[Signature: Illegible] 03-12-98

5 NON-CLINICAL PHARMACOLOGY, TOXICOLOGY, AND ABSORPTION,

5.3.2 Overview ................................................................................................................... 1

Table 1. Summary of Dexmedetomidine Pharmacokinetic Data in Animals .................. 38

Table 2. Summary of Pharmacokinetic Parameters for Dexmedetomidine in

Table 3. Summary of Pharmacokinetic Parameters for Dexmedetomidine in

Table 4. Summary of Pharmacokinetic Parameters for Dexmedetomidine in

Table 5. Summary of [3H]Dexmedetomidine Metabolism in Animals and

Table 6. Excretion Data for the [3H]Dexmedetomidine Dose in Animals and

Table 7. Summary of Urinary Excretion of [3H]Dexmedetomidine and

Table 8. Summary of Fecal and Biliary Excretion of [3H]Dexmedetomidine

Table 9. Summary of Pharmacokinetic and Metabolism Results in Rats Given

Table 10. Distribution of Radioactivity in Tissues of Rats after an Intravenous

Table 11. Summary of Metabolism Results in Rats Given

Table 12. Summary of Metabolism Results in Rats Given

Table 14. Summary of Pharmacokinetic and Metabolism Results in Dogs Given

Table 15. Summary of Metabolism Results in Dogs Given

Table 16. Summary of Metabolism Results in Dogs Given

Table 17. Summary of Pharmacokinetic and Metabolism Results in Humans

Table 18. Summary of Pharmacokinetic and Metabolism Results in Humans

Table 19. Summary of Pharmacokinetic and Metabolism Results in Humans

Dexmedetomidine-HCl (Abbott-85499.1) is a specific and selective α2-adrenoreceptor

5.3.2.2 Absorption and Pharmacokinetics

Total radioactivity appeared to be well absorbed following 20 µg/kg subcutaneous doses of

5.3.2.3 Protein Binding

The in vitro plasma protein binding of [3H]dexmedetomidine was determined with an

[3H]Dexmedetomidine was bound to physiological concentrations of both human serum

In vitro protein binding interaction studies in human plasma between [3H]dexmedetomidine

Red Blood Cell Binding

In vitro studies with [3H]dexmedetomidine at concentrations of 0.5 and 5 ng base/mL

Tissue Distribution In Rat

Placental and Lacteal Transfer

After a subcutaneous 15 µg/kg dose of [3H]dexmedetomidine to 18 day gravid rats,

Following administration of a subcutaneous 15 µg/kg dose of [3H]dexmedetoraidine to

5.3.2.5 Metabolic Pathways

The NADPH-dependent oxidative metabolism of [3H]dexmedetomidine was also examined

5.3.2.7 Human and Interspecies Comparison

In rats, dogs and humans, intravenous and/or subcutaneous doses of [3H]dexmedetomidine

Under the experimental conditions described, dexmedetomidine metabolic pathways were

Relative Dexmedetomidine Pathways

Prominent metabolic pathways in humans were N-glucuronidation (G-Dex-1 and G-Dex-2)

A 20 µg/kg intravenous or subcutaneous dose of [3H]dexmedetomidine was well absorbed in

Although concentrations of radioactivity in pigmented (7.23 ng Eq/g) and non-pigmented

After a subcutaneous 15 µg/kg dose of [3H]dexmedetomidine to an 18 day gravid rat,

Dexmedetomidine is extensively metabolized in rats primarily by oxidative and conjugative

5.3.3.3 Absorption and Pharmacokinetics

Total radioactivity from subcutaneous 20 µg/kg doses of [3H]dexmedetomidine was rapidly

Tentatively identified circulating metabolites after administration of an intravenous or

5.3.3.4 Protein Binding

In vitro studies using an ultrafiltration technique demonstrated [3H]dexmedetomidine was

5.3.3.6 Placental and Lacteal Transfer

After a subcutaneous 15 µg/kg dose of [3H]dexmedetomidine to 18 day gravid rats,

Following administration of a subcutaneous 15 µg/kg dose of [3H]dexmedetomidine to

5.3.3.7 Metabolic Pathways

[3H]Dexmedetomidine is extensively metabolized in rats by Phase I (oxidative) and Phase II

In vitro studies in rats demonstrated that the OH metabolite of dexmedetomidine,