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Drug interactions in dentistry: The

importance of knowing your CYPs


ELLIOT V. HERSH and PAUL A. MOORE
J Am Dent Assoc 2004;135;298-311

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C L I N I C A L PHARMACOLOGY ABSTRACT
Background. The hepatic and intestinal
cytochrome, or CY, P450
A D A
COVER STORY enzyme system is respon- J
sible for the biotransforma- ✷ 

Drug interactions tion of a multitude of

N
CON

IO
drugs. Certain medications

T
T

A
used in dentistry can act N

I
in dentistry
C
A UING EDU 1
as substrates, inducers or RT
inhibitors of this system. ICLE
The importance of knowing Methods. The authors
conducted a MEDLINE search of articles
your CYPs appearing between 1976 and the present
using the keywords “drug interactions” and
“cytochrome P450,” and reviewed reports
ELLIOT V. HERSH, D.M.D., M.S., Ph.D.; involving dental therapeutic agents using
PAUL A. MOORE, D.M.D., Ph.D., M.P.H. PubMed links from an Indiana University

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CYP450 drug interaction table on the World
Wide Web.
s new drugs reach the marketplace and Results. The antibiotics erythromycin and

A patients take an increasing number and clarithromycin are potent inhibitors of


variety of pharmaceutical agents for a host of CYP3A4 and can increase blood levels and
medical conditions, the potential for serious toxicity of CYP3A4 substrates. Likewise,
drug interactions continues to grow.1 The quinolone antibiotics such as ciprofloxacin
hepatic and intestinal cytochrome, or CY, P450 enzyme inhibit the metabolism of CYP1A2 sub-
system is responsible for the biotransformation of a mul- strates. Other dental therapeutic agents are
titude of drugs. As it is important for children to learn substrates for CYP2C9 (celecoxib, ibuprofen
their ABCs, it is becoming equally and naproxen), CYP2D6 (codeine and tra-
madol), CYP3A4 (methylprednisolone) and
Acquiring important for dentists to learn their
CYP2E1 (acetaminophen). Because codeine
knowledge of CYPs, to lessen the chances of severe and tramadol are prodrugs, inhibition of their
drug interactions’ appearing in their
the cytochrome metabolism can lead to a diminution of their
patients.
P450 system The CYP450 system is a group of analgesic effects. While inducers of
will help heme-containing enzymes embedded pri- acetaminophen metabolism, including
alcohol, theoretically can increase the propor-
practitioners marily in the lipid bilayer of the endo-
tion of it that is biotransformed into a poten-
avoid plasmic recticulum of hepatocytes
tially hepatotoxic metabolite, recent research
potentially within the liver and2 enterocytes within suggests that concomitant alcohol intake does
the small intestine. CYP enzymes are
serious not increase the hepatotoxic potential of ther-
involved in the oxidative metabolism of
adverse drug a number of drug classes, as well as of a apeutic doses of acetaminophen.
interactions. variety of endogenous substances, Conclusions. A number of clinically sig-
including prostaglandins and steroid nificant drug interactions can arise with
hormones. dental therapeutic agents that act as sub-
The current nomenclature of these enzymes is three- strates or inhibitors of the CYP450 system.
tiered: CYP followed by a number representing the Clinical Implications. As polyphar-
family of enzymes, a letter representing the subfamily macy continues to increase, the likelihood of
and then another number representing the individual adverse drug interactions in dentistry will
gene (for instance, CYP3A4).2,3 Each enzyme is termed increase as well. Ensuring that patients’
an “isoform” or “isoenzyme.” More than 30 CYP450 medical histories are up to date and
isoenzymes have been identified to date; the major ones acquiring knowledge of the various sub-
responsible for drug metabolism are CYP1A2, CYP2C9, strates, inducers and inhibitors of the
CYP2C19, CYP2D6, CYP2E1 and CYP3A4. The human CYP450 system will help practitioners
CYP3A4 isoform is the most abundant cytochrome avoid potentially serious adverse drug
interactions.

298 JADA, Vol. 135, March 2004


Copyright ©2004 American Dental Association. All rights reserved.
C L I N I C A L PHARMACOLOGY

TABLE 1

SOME SUBSTRATES FOR CYTOCHROME P450 ISOENZYMES.


ISOENZYME SUBSTRATE

CYP1A2 Anesthetic agent, local: ropivacaine


Anti-Alzheimer agent: tacrine
Antiasthmatic agents: theophylline, zileuton
Antidepressant agents: amitriptyline, clomipramine, fluvoxamine, imipramine
Antipsychotic agents: clozapine, haloperidol

CYP2C9 Angiotensin II receptor blockers: irbesartan, losartan


Anticoagulant agent: warfarin
Anticonvulsant agent: phenytoin
Cancer chemotherapeutic agent: tamoxifen
Hypoglycemic agents, oral: glipizide, glyburide, tolbutamide
NSAIDs*: celecoxib, diclofenac, ibuprofen, naproxen

CYP2C19 Antidepressant agents: amitriptyline, citalopram, clomipramine, imipramine


Benzodiazepine: diazepam
Immunosuppressant agent: cyclophosphamide (prodrug)
Proton pump inhibitors: lansoprazole, omeprazole, pantopropazole

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CYP2D6 Analgesic agents, narcotic: codeine (prodrug), tramadol (prodrug)
Anesthetic agent, local: lidocaine
Antidepressant agents: amitriptyline, clomipramine, desipramine, imipramine,
paroxetine
Antipsychotic agents: haloperidol, perphenazine, risperidone
Beta blockers: carvedilol, metoprolol, propranolol, timolol

CYP2E1 Analgesic agent, nonnarcotic: acetaminophen


Anesthetic agents, general: enflurane, halothane, isoflurane, sevoflurane
Muscle relaxant: chlorzoxazone
Recreational drug: ethanol

CYP3A4 Analgesic agent, narcotic: alfentanil


Anesthetic agent, local: lidocaine
Antibiotic agents: clarithromycin, erythromycin
Anticoagulant agent: warfarin
Anticonvulsant agent: carbamazepine
Antihistamine agents: astemizole,† terfenadine†
Antipsychotic agents: haloperidol, pimozide
Benzodiazepine agents: alprazolam, diazepam, midazolam, triazolam
Calcium channel–blocking agents: amlodipine, diltiazem, felodipine,
nifedipine, verapamil
Cholesterol-lowering drugs: atorvastatin, cerivastatin,† lovastatin (prodrug),
simvastatin (prodrug)
Corticosteroids: hydrocortisone, methylprednisolone
HIV protease inhibitors: idinavir, nelfinivir, ritonavir, saquinavir
Hormonal agents: estradiol, progesterone
Immunosuppressant agents: cyclosporine, tacrolimus
Prokinetic agent: cisapride†

* NSAIDs: Nonsteroidal anti-inflammatory drugs.


† No longer available in the United States.

family expressed in the human liver and intes- greatly improved the quality and longevity of life
tine, and thus is involved in the metabolism of a in patients infected with the virus—are sub-
greater number of drugs and a greater proportion strates for CYP3A4.5,6
of adverse drug-drug interactions than are other Inducers of a specific CYP450 isoform (Table 2)
CYP isoforms.4 increase the amount and subsequent activity of
A substrate is a drug or endogenous compound that particular enzyme in hepatic and small
that is metabolized by a particular CYP450 iso- intestinal tissue, potentially leading to dimin-
form. Some substrates for the various CYP450 ished plasma levels of active drugs that are sub-
isoforms are illustrated in Table 1.4,5 For example, strates for that enzyme.2,3,5 In patients with HIV
the HIV protease inhibitors idinavir, nelfinivir, who take protease inhibitors, the concomitant
ritonavir and saquinavir—which, when combined intake of the herbal antidepressant St. John’s
with reverse transcriptase inhibitors, have wort, which is available without a prescription,

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Copyright ©2004 American Dental Association. All rights reserved.
C L I N I C A L PHARMACOLOGY

TABLE 2 to mask the taste of


ethanol.9
SOME INDUCERS OF CYTOCHROME P450 ISOENZYMES. The purpose of this
ISOENZYME INDUCER
article is to introduce
readers to some of the
CYP1A2 Antibiotic agent: rifampin more clinically relevant
Anticonvulsant agent: carbamazepine adverse drug interac-
Antidiabetic agent: insulin
Foods: chargrilled meats tions involving the
Recreational drugs: tobacco CYP450 system that
CYP2C9 Antibiotic agent: rifampin could appear in dental
Barbiturates: phenobarbital, secobarbital practice. An excellent
CYP2C19 Antibiotic agent: rifampin and continually
Anticonvulsant agent: carbamazepine updated table of
Hormonal agent: norethindrone
CYP450 substrates,
CYP2D6 Antibiotic agent: rifampin inducers and inhibitors,
Corticosteroid: dexamethasone
with links to key arti-
CYP2E1 Antibiotic agent: isoniazid cles and PubMed, can

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Recreational drugs: ethanol, tobacco
be found on the World
CYP3A4 Antibiotic agents: rifabutin, rifampin Wide Web.5
Anticonvulsant agents: carbamazepine, phenytoin
Barbiturates: phenobarbital, secobarbital
Corticosteroids: dexamethasone, hydrocortisone, prednisolone, METHODS
methylprednisolone
Herbal remedy: St. John’s wort We conducted a search
HIV antiviral agents: efavirenz, nevirapine on MEDLINE of arti-
Oral hypoglycemic agents: pioglitazone, troglitazone
cles appearing between
1976 and the present
significantly decreases blood levels and the employing the keywords “drug interactions” and
antiviral efficacy of these drugs because St. “cytochrome P450” and reviewed reports
John’s wort is a potent inducer of CYP3A4.7 involving dental therapeutic agents. In addition,
On the other hand, enzyme we reviewed PubMed links for
inhibitors (Table 3) reduce the interactions involving dental thera-
activity of a specific CYP450 iso- Enzyme inhibitors peutic agents as found on the
form, resulting in an accumulation Cytochrome P450 Drug Interaction
reduce the activity of
of the substrate drug.2,3,5 The toxicity Table posted on the World Wide
typically encountered is identical to a specific cytochrome Web by the Indiana University
what would be seen from an over- P450 isoform, School of Medicine’s Division of
dose of the substrate drug. With resulting in an Clinical Pharmacology.5
CYP3A4, it is not only drugs that accumulation of the
can inhibit this isoform, but also RESULTS
substrate drug.
grapefruit juice, a seemingly A number of drugs used in dental
innocuous food product.5,8-10 It practice can be involved in adverse
appears that bergamottin, a furan- drug-drug interactions as sub-
coumarin, and possibly some other related com- strates, inducers or inhibitors of the CYP450
pounds found in grapefruit juice both inhibit the system. This article will discuss the clinical sig-
action of and reduce hepatic and intestinal con- nificance of these interactions.
centrations of CYP3A4,11,12 causing the accumula- Interactions involving CYP450 substrates.
tion of a number of CYP3A4 substrates. The Benzodiazepines. Alprazolam, diazepam, mida-
ability of grapefruit to lead to excessive plasma zolam and triazolam are substrates for CYP3A4,
concentrations of CYP3A4 substrates first was with diazepam being a substrate for CYP2C19 as
described for calcium channel antagonists, where well. These drugs possess a wide therapeutic
excessive blood levels can lead to hypotension and index, and it is for this reason that they now are
peripheral edema.9,13 This was a serendipitous the most widely used oral and injectable anxi-
finding (as so many scientific discoveries are); olytic agents in all of dental medicine.14 While
grapefruit juice was being used in the study only drug interactions with benzodiazepines theoreti-

300 JADA, Vol. 135, March 2004


Copyright ©2004 American Dental Association. All rights reserved.
C L I N I C A L PHARMACOLOGY

TABLE 3

SOME INHIBITORS OF CYTOCHROME P450 ISOENZYMES.


ISOENZYME INHIBITOR

CYP1A2 Antibiotic agents: ciprofloxacin, enoxacin, erythromycin, ofloxacin


Antidepressant agent: fluvoxamine
Antiplatelet agent: ticlopidine
H2 receptor blocker: cimetidine

CYP2C9 Antibiotic agents: isoniazid, metronidazole, sulfamethoxazole, trimethoprim


Antidepressant agents: fluvoxamine, paroxetine, sertraline
Antidysrhythmic agent: amiodarone
Antifungal agents: fluconazole, miconazole

CYP2C19 Anticonvulsant agent: felbamate


Antidepressant agents: fluoxetine, fluvoxamine, paroxetine
Antifungal agent: ketoconazole
Antiplatelet agent: ticlopidine
Proton pump inhibitors: lansoprazole, omeprazole

CYP2D6 Antidepressant agents: fluoxetine, paroxetine, sertraline

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Antidysrhythmic agents: amiodarone, quinidine
H1 receptor blockers: chlorpheniramine, hydroxyzine, promethazine
H2 receptor blockers: cimetidine, ranitidine
NSAID*: celecoxib
Recreational drug: cocaine

CYP2E1 Alcoholism rehabilitation drug: disulfiram

CYP3A4 Antibiotic agents: ciprofloxacin, clarithromycin, erythromycin, norfloxacin


Antidepressant agents: fluvoxamine, nefazodone
Antidysrhythmic agent: amiodarone
Antifungal agents: fluconazole, itraconazole, ketoconazole
Calcium-channel blockers: diltiazem, verapamil
Food product: grapefruit juice
H2 receptor blocker: cimetidine
HIV protease inhibitors: idinavir, nelfinivir, ritonavir, saquinavir

* NSAID: Nonsteroidal anti-inflammatory drug.

cally can involve inducers and inhibitors of these zolam has been reported to increase the sedative
specific CYP450 isoforms, those involving effects of the benzodiazepine.18 By their ability to
inhibitors of CYP3A4 are of most concern to the inhibit CYP3A4, azole antifungal drugs,4,19-21 pro-
clinician. Like most interactions involving the tease inhibitors (Figure 2),6,16,22 the selective sero-
CYP450 system, interactions involving benzodi- tonin reuptake blocker fluvoxamine and the
azepines are more likely to occur with the oral serotonin-2 receptor antagonist nefezadone (both
administration of these drugs. These particular antidepressants)23 and grapefruit juice24,25 all have
drug interactions have been well-documented; the been shown to significantly increase blood levels,
end result is benzodiazepine accumulation and elimination half-lives and the sedative and
prolonged and excessive sedation.15,16 The psychomotor impairment effects of diazepam,
macrolide antibiotics erythromycin and clar- alprazolam, midazolam and triazolam.
ithromycin, which are used widely in dentistry, Narcotic analgesics. Codeine and tramadol are
are potent inhibitors of CYP3A4. In one placebo- substrates for CYP2D6. They can be prescribed
controlled study,17 erythromycin at 500 mil- for the control of postoperative pain as single
ligrams three times per day for six days increased entities or in combination with aspirin (codeine)
peak blood levels of a single dose of oral mida- or acetaminophen (both codeine and tramadol). In
zolam almost threefold (Figure 1). In addition, the outpatient dental setting, combining mini-
drowsiness and other indicators of psychomotor mally effective doses of these agents (60 mg of
impairment were far more intense in patients codeine or 75 mg of tramadol) with optimal or
taking erythromycin for six days than in those near-optimal doses of aspirin or acetaminophen
taking a placebo.17 Even a single dose of eryth- (600-1,000 mg) usually will provide better anal-
romycin taken concomitantly with oral mida- gesia with fewer side effects than will simply

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Copyright ©2004 American Dental Association. All rights reserved.
C L I N I C A L PHARMACOLOGY

PEAK MIDAZOLAM CONCENTRATION (ng/mL) 200 40

180 35
N = 12 N = 10
160

(HOURS)
30 (P < .005)
(P = .003)
140
25
120

2
1
ALPRAZOLAM T
100 20

80 15

60
10
40

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5
20

0 0
Placebo Erythromycin Placebo Ritonavir

DOSE DOSE

Figure 1. Effects of placebo or erythromycin 500 mil- Figure 2. Effects of placebo or the protease inhibitor
ligrams taken three times per day for six days on peak ritonavir on the half-life of alprazolam. Alprazolam’s
plasma levels (mean ± standard error) of a single oral half-life was 13 hours after taking placebo and 30 hours
dose of midazolam 15 mg. Blood levels of midazolam after taking ritonavir (P < .005). Data adapted from
were approximately threefold higher in the erythromycin Greenblatt and colleagues.22
group (P = .003). Data adapted from Olkkola and col-
leagues.17 ng/mL: Nanograms per milliliter.

administering a higher dose of the narcotic high degree of genetic polymorphism.28,30 From a
alone.26,27 Both agents are prodrugs; that is, the clinical perspective, this means that there are
parent compound is essentially devoid of anal- patients in the population who either poorly or
gesic activity but the active demethylated extensively metabolize CYP2D6 substrates. With
metabolites—morphine in the case of codeine and prodrugs like codeine and tramadol, people who
O-demethyl tramadol in the case of tramadol— metabolize them poorly exhibit little analgesic
are responsible for the analgesic activity.28,29 The activity with the intake of these drugs because
CYP450 isoform responsible for this conversion is they do not form the necessary active metabolites,
CYP2D6 (Figure 3). It has been demonstrated while people who metabolize them extensively
with both drugs that the administration of the readily form the active metabolites and exhibit
antidysrhythymic agent quinidine, a known significant analgesia.28 Up to 10 percent of the
CYP2D6 inhibitor, essentially abolishes their white population are thought to metabolize
analgesic activity.28,30 Other widely prescribed CYP2D6 substrates poorly.5 While this issue is
CYP2D6 inhibitors—including antidepressant outside the scope of clinical practice, it is possible
agents of the selective serotonin reuptake that in the future, a simple blood test for CYP2D6
inhibitor class (fluoxetine, paroxetine and sertra- activity could be used to predict a patient’s likely
line) and the cyclo-oxygenase-, or COX-, 2– response to either agent.
selective nonsteroidal anti-inflammatory drug, or Lidocaine. Lidocaine, the most frequently used
NSAID, celecoxib—have the theoretical potential local anesthetic in all of dentistry, is a substrate
to diminish the analgesic effects of both codeine for both CYP2D6 and CYP3A4.5 Because two
and tramadol. The clinical significance of these CYP450 isoforms control the drug’s metabolism,
interactions needs to be explored. dramatic increases in lidocaine blood levels are
One other intriguing discovery with important unlikely to occur by the inhibition of a single
clinical implications is that CYP2D6 exhibits a isoform (for example, inhibition of CYP3A4 by

302 JADA, Vol. 135, March 2004


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C L I N I C A L PHARMACOLOGY

CH3 CH3 CH3 CH3


N-CH3 N-CH3
N N
CH2 CH2

OH OH
CYP2D6 CYP2D6
CH3O O HO O CH3O HO
Codeine Morphine
Tramadol O-Demethyl Tramadol
A B
Figure 3. The demethylation of selected prodrugs to the active metabolites morphine and O-demethyl tramadol by
CYP2D6. A. Codeine. B. Tramadol.

erythromycin). Four doses of erythromycin ethyl- and an increased likelihood of toxicity. However,
succinate 600 mg given over two days modestly it appears that other CYP450 isoforms also play a
increased the half-life of an intravenous lidocaine role in NSAID metabolism,38-40 so that inhibitors
31
infusion from 2.2 to 2.8 hours. Of interest to of the single CYP2C9 isoform should not cause
pediatric dentists, who frequently use antihis- dramatic increases in blood levels or half-lives of
tamines in sedative premedication regimens, the these NSAIDs, especially after short-term dosing
CYP2D6 inhibitors diphenhydramine and chlor- for acute pain.

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pheniramine impaired lidocaine metabolism in Acetaminophen. Acetaminophen is the most
rodent hepatocytes.32 However, the ability of clas- widely sold over-the-counter, or OTC, analgesic-
sical antihistamines to increase blood levels of a antipyretic agent in the United States.41 In addi-
single dose of lidocaine after a tion to OTC sales, the number of
dental injection never has been prescriptions dispensed in 2002 for
demonstrated in humans. In addi- The ability of classical acetaminophen-narcotic combina-
tion, computer-simulated plasma tion drugs containing hydrocodone,
antihistamines to
concentration curves after the codeine, propoxyphene and oxy-
injection of a single cartridge of 2 increase blood levels codone were ranked first, 32nd, 37th
percent lidocaine plus 1:100,000 of a single dose of and 86th, respectively, of all pre-
epinephrine revealed that even a lidocaine after a scribed medications in the United
doubling of lidocaine’s half-life dental injection States.42 When used for the short-
increased plasma concentrations by never has been term treatment of pain or fever
only 9 percent.16 The most impor- according to package insert guide-
demonstrated in
tant ways to avoid local anesthetic lines (maximum adult dose of 4
toxicity in the outpatient dental humans. grams per day), acetaminophen
setting are to use good aspirating probably is the safest of all the non-
techniques and to adhere strictly to prescription analgesic agents.36,43
maximum recommended dosage guidelines.33,34 However, acute overdoses of acetaminophen—
NSAIDs. The NSAIDs celecoxib, diclofenac, typically, 15 g or more in an adult—frequently
ibuprofen and naproxen are all substrates of result in hepatotoxicity.36,44 In addition, multiple
CYP2C9. As a group, NSAIDs are generally effi- excessive dose miscalculations administered to
cacious and well-tolerated for the short-term febrile pediatric patients by their parents also
treatment of postsurgical dental pain.35,36 As pre- have led to severe hepatotoxicity.45 In the case of
viously described for the CYP2D6 substrates overdose, an electrophilic toxic metabolite N-
codeine and tramadol, there is a growing interest acetyl-p-benzoquinoneimine, or NAPQI, accumu-
in genetic polymorphisms of CYP2C9.37-39 How- lates, resulting in hepatic cell death.44
ever, because these NSAIDs are not prodrugs, When therapeutic doses of acetaminophen are
people who metabolize them poorly would be consumed, approximately 96 percent undergoes
more prone to active drug accumulation and toxi- conjugation in the liver via the addition of a sul-
city (renal and gastrointestinal) with chronic fate or glucuronic acid group leading to the forma-
dosing than would those who metabolize them tion of inactive-nontoxic metabolites (Figure 4).
extensively.37 Theoretically, drugs that are Via CYP2E1, the remaining 4 percent is con-
inhibitors of CYP2C9 (Table 3) also could impair verted to the highly reactive hepatotoxic metabo-
the metabolism and subsequent elimination of lite NAPQI.44,46 However, this compound rapidly
these four NSAIDs, leading to drug accumulation combines with glutathione stores in the liver and

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Copyright ©2004 American Dental Association. All rights reserved.
C L I N I C A L PHARMACOLOGY

abuse.47 Surprisingly, even with the restrictive


labeling and dosing of acetaminophen in combina-
HO NHCOCH3
tion with alcohol, the interaction is not well-
Glucuronidation
supported by scientific research.
or Sulfation Acetaminophen CYP2E1 (4%) As shown in Tables 1 and 2, ethanol can act as
(96%)
both a substrate and an inducer of CYP2E1.5,44
Below blood levels of 250 milligrams per deciliter,
ethanol preferentially occupies CYP2E1 over
RO NHCOCH3 O NHCOCH3
other substrates, resulting in the formation of
Glutathione ethanol metabolites while limiting its associa-
Conjugated Metabolite N-acetyl-p-benzoquinoneimine tion with other substrates, including acetamino-
(NAPQI)
phen.44,46,49 At concentrations greater than 250
mg/dL, there also appears to be some de novo syn-
Figure 4. Metabolic fate of acetaminophen. The vast
majority of acetaminophen undergoes conjugation to
thesis of CYP2E1, but experimental and com-
inactive, nontoxic metabolites; “R” represents glucuronic puter models have revealed that even when maxi-
acid or sulfate. Approximately 4 percent of the parent mally induced, the production of NAPQI from
compound is converted to the hepatotoxic metabolite
acetaminophen is increased only twofold.44 It has

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N-acetyl-p-benzoquinoneimine which at therapeutic doses
of acetaminophen rapidly combines with glutathione been estimated that approximately 0.635 g of
stores in the liver and is inactivated.
NAPQI must be produced in a 150-pound adult to
reach the threshold of liver toxicity. This is based
essentially is rendered harmless.46 In the case of a on the facts that approximately 4 percent of a
massive acetaminophen overdose, the excessive given acetaminophen dose is converted to NAPQI
production of NAPQI overwhelms the hepatic glu- and an acute intake of 15.9 g of acetaminophen is
tathione stores, resulting in alkylation of hepatic needed to reach the threshold of liver toxicity
proteins and irreversible cellular damage unless (0.04 × 15.9 g acetaminophen = 0.635 g NAPQI).44,50
the antidote N-acetylcysteine is administered If one extrapolates these calculations to a patient
within the first 16 hours (before symptoms of the consuming a full 1-g therapeutic dose of
overdose become clinically evident).36,44 acetaminophen, and having a high blood alcohol
Since CYP2E1 is an inducible enzyme, there level, the maximum concentration of NAPQI
has been great concern over the possibility that formed would only be 0.080 g (2 × 0.04 × 1 g), or
drugs that are inducers of this enzyme, particu- approximately eightfold less than needed to reach
larly ethanol, could promote the conversion of the threshold of hepatotoxicity.
acetaminophen to NAPQI, even in patients taking The simultaneous ingestion of alcohol has
therapeutic doses of the analgesic.46 An even been shown to exert a hepatoprotective effect
greater concern regarding acetaminophen hepato- in patients taking massive overdoses of
toxicity has been voiced for patients with alco- acetaminophen.44,46,51 In one such case, a patient
holism. The thought is that not only could ingested what usually is a lethal dose of 60 g of
CYP2E1 be induced in these patients, but also acetaminophen after 48 hours of heavy drinking
glutathione, which normally inactivates NAPQI, of alcohol—and survived with little evidence of
is known to be depleted in patients with alco- hepatotoxicity.52 In this situation, alcohol prob-
holism, further increasing the likelihood of ably occupied a large proportion of the hepatic
serious hepatotoxicity.36,46,47 Current U.S. Food CYP2E1, limiting the association of
and Drug Administration-, or FDA-, approved acetaminophen with the enzyme and the subse-
labeling of OTC acetaminophen products reflects quent production of NAPQI.36,46,49
this concern; stating that “patients who consume With regard to patients with alcoholism taking
three or more alcoholic drinks per day should con- therapeutic doses of acetaminophen, a review of
tact their physician before ingesting more than 2,000 reports revealed that Class I
acetaminophen, because the combination may (controlled, randomized, blinded clinical trials)
increase the risk of liver damage.”48 In addition, and Class II (prospective nonrandomized or non-
published recommendations limit the maximum blinded trials or well-designed case-control
daily dose of acetaminophen to only 2 g in studies) data demonstrated little toxicity with the
patients with alcoholism to avoid additional liver combination.44,53 On the other hand, some Class
damage that is already present due to alcohol III data relying exclusively on patient recall (ret-

304 JADA, Vol. 135, March 2004


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C L I N I C A L PHARMACOLOGY

rospective case series, single case studies) sug- dicted to be involved in numerous adverse drug
gested that “a morbid fate awaits some alcoholic interactions,57 in which their concomitant admin-
patients who ingest a therapeutic dose of istration would significantly reduce blood levels of
acetaminophen.”44 Thus, we are left with con- many CYP3A4 substrates. However, this predic-
flicting results: well-designed reports suggesting tion has not been borne out in clinical studies.56,57
little concern regarding using therapeutic doses of More important from a clinical perspective is
acetaminophen in these patients, and purely ret- that because corticosteroids are substrates of
rospective cases suggesting a high likelihood of CYP3A4, their blood levels could become elevated
toxicity. It appears that some patients with alco- and their half-lives significantly increased when
holism who ingest massive overdoses of an inhibitor of this enzyme is administered con-
acetaminophen (median dose of 54 g) may be at comitantly. This, in turn, would lead to an
greater risk of experiencing death than nonalco- increased potential for corticosteroid toxicity,
holic patients who ingest similar amounts of including unwanted immunosuppression, sup-
acetaminophen. The patient with chronic alco- pression of the hypothalamic-pituitary-adrenal
holism may have decreased synthetic rates of a axis and hyperglycemia. The corticosteroid that
protein transporter that moves glutathione from seems most prone to these interactions is methyl-
the hepatic cytosol into the mito- prednisolone,58-64 an agent fre-

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chondria. Since the mitochondria quently administered in a six-day,
are targeted by NAPQI, this may Some patients with 21-dose regimen (a dose-pack) to
explain the increased toxicity of an reduce postoperative swelling after
alcoholism who ingest
acetaminophen overdose in the dental impaction surgery.
patient with alcoholism.44 The FDA massive overdoses of CYP3A4-inhibitor drugs that have
continues to hold hearings on the acetaminophen may been documented to cause the
issue of alcohol and acetaminophen be at greater risk of accumulation of methylpred-
interactions; it can be hoped that experiencing death nisolone include the macrolide
future revisions to its acetamino- than nonalcoholic antibiotic drugs erythromycin and
phen monograph (and, in fact, the clarithromycin,58,59 the azole anti-
patients who ingest
monographs for all OTC analgesic fungal drugs itraconazole and keto-
agents with respect to alcohol con- similar amounts of conazole,60,61 the calcium-
sumption) will be based on evidence acetaminophen. channel–blocking agents diltiazem
and not solely on the results of and mibefradil62,63 and 200 mL of
54
unsubstantiated case reports. double-strength grapefruit juice.64
Corticosteroids. Corticosteroids It is likely that other CYP3A4
such as dexamethasone and methylprednisolone inhibitors also could interact adversely with
are potent anti-inflammatory and immunosup- methylprednisolone. Clinicians should be aware
pressant agents. They frequently are used for a of these potential interactions and advise patients
host of chronic inflammatory and autoimmune to avoid the ingestion of grapefruit juice during
diseases, including asthma, ulcerative colitis and their course of methylprednisolone therapy and
lupus erythematosus and, in combination with for at least three days afterward.
other immunosuppressant agents, in the preven- Interactions involving CYP450 inducers.
tion of organ transplant rejection.55 In dentistry, Barbiturates. Derivatives of barbituric acid,
therapeutic uses of glucocorticoids include the including phenobarbital and secobarbital, once
reduction of swelling after oral surgery proce- were important drugs in oral sedation techniques
dures, the treatment of temporomandibular joint used with anxious dental patients. However,
syndrome symptoms (often by localized injection), because of their low therapeutic index, high abuse
the topical treatment of various oral-mucosal potential, disruptions of rapid-eye-movement–
lesions and as “stress steroids” in patients whose stage sleep and the potential for numerous drug
hypothalamic-pituitary-adrenal axis is sup- interactions, they have been replaced largely by
pressed.55 The actions of corticosteroids on the benzodiazepines.14,65 Barbiturates are known to
CYP450 system are complex, and various drugs of induce various isoforms of the CYP450 systems,
the class can act as both substrates and inducers including CYP2C9 and CYP3A4, leading to a
of CYP3A4 isoform5,56 (Tables 1 and 2). As decrease in blood levels of a number of drugs.
inducers of CYP3A4, these agents could be pre- This has been documented for the antidys-

JADA, Vol. 135, March 2004 305


Copyright ©2004 American Dental Association. All rights reserved.
C L I N I C A L PHARMACOLOGY

rhythmic agent quinidine, azole antifungal 500 mg twice per day for 10 days) is becoming
agents, nifedipine and other calcium-channel increasingly popular in the treatment of refrac-
blockers, the cancer chemotherapeutic agent tory periodontal infections that harbor Acti-
etoposide, oral contraceptive agents containing nobacillus actinomycetemcomitans and other
estradiol and progesterone, the immunosuppres- gram-negative, facultatively anaerobic rods.68-70
sant agents cyclosporine and tacrolimus, various Ciprofloxacin is a potent inhibitor of CYP1A2 and
HIV protease inhibitors, methadone and war- also produces some inhibition of CYP3A4. The
farin, among others.2,3,66 Acute (single-dose) barbi- most clinically significant interaction involving
turate therapy that typically was used in dental ciprofloxacin is its ability to inhibit the
sedative techniques probably was only rarely metabolism of the CYP1A2 substrate theo-
involved in adverse drug interactions involving phylline.71,72 While increases in theophylline blood
the induction of the CYP450 system, because concentrations and half-life average only about 20
induction typically takes at least several days of to 30 percent, the drug has a rather low thera-
barbiturate use.2 Longer-term therapy, such as peutic index. Cardiac dysrhythmias and convul-
sometimes used for temporomandibular joint dys- sions are the most serious consequence of exces-
function and headache,67 indeed sive blood levels of theophylline.
could cause blood levels of these It has been reported that a reg-

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drugs to fall below therapeutic Clinicians are imen of ciprofloxacin 250 mg taken
levels. For example, a patient cautioned to twice per day for seven days
taking cyclosporine or tacrolimus recognize increased average plasma concen-
because of an organ transplant the- brand-name drugs trations of the atypical antipsy-
oretically could experience acute chotic agent clozapine (a CYP1A2
with ‘hidden’
rejection of that organ. Likewise, a substrate) by approximately 30 per-
patient taking oral contraceptives barbiturate cent.73 In one patient, a regimen of
could begin ovulating and become components. ciprofloxacin 500 mg twice per day
pregnant while receiving barbitu- increased plasma concentrations of
rate therapy. To avoid drug inter- clozapine by 80 percent.74 Elevated
actions of this type, clinicians also are cautioned plasma clozapine levels increase the risk of
to recognize brand-name drugs with “hidden” bar- oversedation, urinary retention, constipation and
biturate components such as the popular seizures in a patient population in which noncom-
migraine drug Fiorinal (Novartis Pharmaceuti- pliance with schizophrenic medication regimens
cals, East Hanover, N.J.), which contains 325 mg already is the norm because of the nature of the
of aspirin plus 50 mg of the barbiturate butal- disease and the unwanted side effects associated
bital. with this class of drugs.75
Interactions involving CYP450 inhibitors. Metronidazole. Metronidazole is highly effec-
Interestingly, the agents used in dental practice tive against obligate anaerobic bacteria associ-
that can act as inhibitors of various CYP450 iso- ated with periodontal disease, periapical
forms all are antimicrobial agents. Antimicrobial abscesses and peri-implantitis.76-79 Because it has
agents are dosed on a more chronic basis than are no activity against facultative anaerobic bacteria,
other therapeutic agents (such as local anesthetic, which can be part of a mixed flora inhabiting
analgesic and anxiolytic agents) routinely used in these infected sites, metronidazole frequently
dentistry, which enhances the likelihood of clini- is combined with a penicillin or with ciproflox-
cally significant CYP450 inhibition and the asso- acin.76-78 With respect to drug interactions,
ciated drug interactions with CYP450 sub- metronidazole is best known for its interaction
strates.15 These interactions as a whole can be with alcohol. This combination can result in a
extremely serious and potentially life-threatening disulfiram-like reaction, which tends to be more
if the substrate drug whose metabolism is being frightening than serious, with patients experi-
inhibited has a low margin of safety or what encing nausea, vomiting, headache and cardiac
pharmacologists call a “low therapeutic index.”1,15 palpitations.15 These symptoms are best explained
Quinolone antibiotic agents. Members of the by metronidazole’s ability to block a key enzyme
quinolone class include ciprofloxacin, enoxacin, in alcohol metabolism, namely acetaldehyde
norfloxacin and ofloxacin. Of these agents, the dehydrogenase, causing acetaldehyde to accumu-
use of systemic ciprofloxacin (typically at a dose of late in the bloodstream after alcohol consumption.

306 JADA, Vol. 135, March 2004


Copyright ©2004 American Dental Association. All rights reserved.
C L I N I C A L PHARMACOLOGY

This adverse drug interaction, however, appears Erythromycin and clarithromycin possess 14
to be unrelated to the inhibition of CYP450 carbon atoms surrounding their macrocyclic lac-
enzymes. tone rings, while azithromycin contains 15 of
Metronidazole also may be involved in other these constituents.89 The primary reason for the
drug interactions that relate to its ability to vast number of potential drug interactions with
inhibit CYP2C9 (Table 3). While a number of sub- CYP3A4 inhibitors is the fact that CYP3A4 has
strates are metabolized by this isoenzyme, the broad substrate specificity and has been esti-
interaction that appears best documented is the mated to contribute to the metabolism of more
ability of metronidazole to significantly increase than 50 percent of all available therapeutic
the blood concentrations, half-life and the associ- agents.57 Since the pharmacokinetic consequences
ated hemorrhagic potential of the anticoagulant of all these interactions is an accumulation of the
agent warfarin.80,81 In addition, metronidazole’s substrate drug, side effects of the substrate drug,
ability to cause the accumulation of the including relatively rare side effects, become more
antiepileptic drug and CYP2C9 substrate pheny- common and more intense. Typically, the more
toin is supported by at least one well-designed chronic the dosing with the substrate and the
clinical trial.82 Excessive phenytoin levels in the inhibitor, the greater the chance for a clinically
blood increase the risk of drowsi- significant drug interaction. How-

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ness, confusion, diplopia, ataxia ever, if the substrate undergoes sig-
and nystagmus.83 Before pre- Metronidazole can nificant (greater than 60 percent)
scribing metronidazole to a dental significantly increase CYP3A4 metabolism in the gut and
patient who is receiving chronic the liver before reaching the sys-
the blood
warfarin or phenytoin therapy, den- temic circulation, the likelihood of a
tists are advised to consult with the concentrations, significant drug interaction
patient’s prescribing physician. half-life and increases, even with just one or two
Macrolide antibiotic agents. His- the associated doses of the substrate drug.8 Exam-
torically, erythromycin was consid- hemorrhagic potential ples of CYP3A4 substrates with rel-
ered to be the antibiotic agent of of the anticoagulant atively low oral bioavailability
choice for patients with penicillin include terfenadine, astemizole,
agent warfarin.
allergies who had odontogenic simvastatin, lovastatin, felodipine
infections.84 However, because of a and midazolam.
high incidence of gastrointestinal complaints, The ability of erythromycin and clarithromycin
increasing bacterial resistance problems and only to inhibit the CYP3A4-directed metabolism of cer-
moderate activity against anerobic bacteria, its tain benzodiazepines15-18 and methylpredniso-
use has been decreasing. Clarithromycin is lone58,59 already has been discussed. Table 4 sum-
better-tolerated than erythromycin; possesses marizes some additional interactions between
better activity against most streptococcal, staphy- CYP3A4 substrates and antimicrobial CYP3A4
lococcal and anaerobic bacterial species; and, inhibitors used in dentistry.86,90-138 Some of these
while more expensive than erythromycin, may substrates—including the nonsedating antihis-
result in better patient compliance because it has tamine agents terfenadine and astemizole, the
to be taken only twice per day.78,84 Like clar- prokinetic agent (gastroesophageal reflux drug)
ithromycin, azithromycin has excellent activity cisapride and the lipid-lowering drug ceriva-
against anaerobes, possesses an extended half-life statin—have been removed from the U.S. market
(requiring only once-per-day dosing) and is an by the FDA, partly because of an unacceptably
alternative to amoxicillin in patients requiring high incidence of usually rare life-threatening
endocarditis-related prophylaxis who are allergic toxicities (torsades de pointes with terfenadine,
to penicillins.85 For this indication, both drugs are astemizole and cisapride and rhabdomyolysis
dosed at 500 mg one hour before the dental with cerivastatin) when administered concomi-
procedure. tantly with CYP3A4 inhibitors.
Erythromycin and clarithromycin are potent Azole antifungal drugs. This group of anti-
inhibitors of CYP3A4 and are associated with fungal agents blocks the fungal CYP450-directed
numerous untoward drug interactions,2,3,5,8,15 while synthesis of the cell membrane component ergos-
azithromycin is not.5,86-88 This difference between terol in sensitive organisms.139 Unfortunately, this
the macrolides probably is structurally related. mechanism of action leads to inhibition of human

JADA, Vol. 135, March 2004 307


Copyright ©2004 American Dental Association. All rights reserved.
C L I N I C A L PHARMACOLOGY

TABLE 4

SOME ADVERSE DRUG:DRUG INTERACTIONS INVOLVING


ERYTHROMYCIN, CLARITHROMYCIN, KETOCONAZOLE AND
ITRACONAZOLE WITH CYP3A4 SUBSTRATES.
CYP3A4 SUBSTRATES POTENTIAL INTERACTION COMMENTS*

Astemizole, Substrate accumulation leading to Torsades de pointes is a life-threatening


Cisapride, cardiac QT interval prolongation ventricular dysrhythmia that occurs in the
Pimozide, and torsades de pointes ventric- setting of electrocardiographic QT interval
Terfenadine ular tachycardia86, 90-100 prolongation. While terfenadine, astemi-
zole and cisapride no longer are available
in the United States, pimozide still is used
in the treatment of psychotic disorders and
is especially effective in the management
of Gilles de la Tourette’s syndrome.100

Substrate accumulation leading to The “statin” drugs inhibit the rate-limiting


Atorvastatin, diffuse myalgias, rhabdomyolysis step (3-hydroxy-3-methyl-glutaryl coen-
Cerivastatin, and renal failure101-106 zyme A, or HMG-CoA, reductase) in

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Lovastatin, cholesterol biosynthesis and are used
Simvastatin widely for this purpose.42 Rhabdomyolysis
is a potentially life-threatening breakdown
of skeletal muscle, resulting in the release
of myoglobin into the serum and urine and
giving the urine a brown-rust color. The
myoglobin can cause blockage of the renal
tubular system, resulting in kidney
damage and acute renal failure.107
Recently, a single case of a possible
fluconazole-simvastatin interaction was
reported.108

Substrate accumulation leading This interaction is an extension of the


Felodipine, to severe hypotension and antihypertensive effects of the substrates.
Nifedipine edema109-111 Other calcium-channel blockers also may
be predisposed to the interaction.

Substrate accumulation leading to This interaction has been used therapeuti-


Cyclosporine, enhanced immunosuppression and cally to reduce the cost of immunosuppres-
Tacrolimus nephrotoxicity112-116 sant therapy.117 Clotrimazole, in the form
of troches—frequently used in the treat-
ment of oral candidiasis—also significantly
increases tacrolimus blood levels.118

Substrate accumulation leading to Fluconazole also increases warfarin blood


Warfarin increased prothrombin times, levels via an inhibition of warfarin’s
international normalized ratios CYP2C9 metabolism.124
and increased risk of serious
bleeding119-123

Substrate accumulation leading to Two cases of a possible fluconazole-


Carbamazepine increased risk of ataxia, vertigo, carbamazepine interaction have been
drowsiness and confusion125-130 reported.131,132

Substrate accumulation leading to This interaction appears to involve only


Theophylline increased risk of tremors, cardiac erythromycin, possibly owing to its ability
dysrhythmias and seizures133-138 to inhibit CYP1A2, of which theophylline
is a substrate.2,138

* The use of alternative antibiotics (penicillin, tetracycline, azithromycin or clindamycin) or antifungals (topical nystatin or amphotericin B)
that are appropriate for the specific infection is advised when patients are taking these CYP3A4 substrates.

CYP450 isoforms, especially CYP3A4. Of this substrates (Table 4). Fortunately, these drugs are
group, ketoconazole and itraconazole are associ- rarely, if ever, used in outpatient dentistry. How-
ated with by far the greatest incidence of adverse ever, caution still is advised when administering
drug interactions, resulting in the accumulation fluconazole or clotrimazole to treat oral candidi-
and subsequent toxicity of a number of CYP3A4 asis in patients taking CYP3A4 substrates.

308 JADA, Vol. 135, March 2004


Copyright ©2004 American Dental Association. All rights reserved.
C L I N I C A L PHARMACOLOGY

Potentially serious interactions have been 19. Yasui N, Kondo T, Otani K, et al. Effect of itraconazole on the
single oral dose pharmacokinetics and pharmacodynamics of alpra-
reported when these agents are administered to zolam. Psychopharmacology (Berl) 1998;139:269-73.
patients taking simvastatin, tacrolimus, warfarin 20. Olkkola KT, Backman JT, Neuvonen PJ. Midazolam should be
avoided in patients receiving the systemic antimycotics ketoconazole or
or carbamazepine.108,118,124,131,132 itraconazole. Clin Pharmacol Ther 1994;55:481-5.
21. Varhe A, Olkkola KT, Neuvonen PJ. Oral triazolam is potentially
CONCLUSIONS hazardous to patients receiving systemic antimycotics ketoconazole or
itraconazole. Clin Pharmacol Ther 1994;56:601-7.
The CYP450 system is responsible for the 22. Greenblatt DJ, von Moltke LL, Harmatz JS, et al. Alprazolam-
ritonavir interaction: implications for product labeling. Clin Pharmacol
metabolism of a multitude of diverse pharmaco- Ther 2000; 67;335-41.
logical agents. Drugs routinely used in dentistry 23. von Moltke LL, Greenblatt DJ, Harmatz JS, et al. Triazolam bio-
transformation by human liver microsomes in vitro: effects of metabolic
often serve as substrates or inhibitors of this inhibitors and clinical confirmation of a predicted interaction with
system. Dentists can avoid untoward drug inter- ketoconazole. J Pharmacol Exp Ther 1996;276:370-9.
24. Goho C. Oral midazolam-grapefruit juice drug interaction.
actions in their practices by gaining an under- Pediatr Dent 2001;23:365-6.
standing of the CYP450 substrates, inducers and 25. Ozdemir M, Aktan Y, Boydag BS, Cingi MI, Musmul A. Interac-
tion between grapefruit juice and diazepam in humans. Eur J Drug
inhibitors. ■ Metab Pharmacokinet 1998;23:55-9.
26. Beaver WT. Aspirin and acetaminophen as constituents of anal-
gesic combinations. Arch Intern Med 1981;141:293-300.
Dr. Hersh is a professor of oral surgery and pharmacology and asso- 27. McQuay H, Edwards J. Meta-analysis of single dose oral tramadol
ciate dean of clinical research, University of Pennsylvania School of plus acetaminophen in acute postoperative pain. Eur J Anaesthesiol

Downloaded from jada.ada.org on April 14, 2010


Dental Medicine, Philadelphia, Pa. 19104-6030, e-mail “evhersh@ 2003;20(supplement 28):19-22.
pobox.upenn.edu”. Address reprint requests to Dr. Hersh. 28. Desmeules J, Gascon MP, Dayer P, Magistris M. Impact of envi-
ronmental and genetic factors on codeine analgesia. Eur J Clin Phar-
macol 1991;41:23-6.
Dr. Moore is a professor of pharmacology and dental public health,
29. Lee CR, McTavish D, Sorkin EM. Tramadol: a preliminary review
University of Pittsburgh School of Dental Medicine, Pittsburgh.
of its pharmacodynamic and pharmacokinetic properties, and thera-
peutic potential in acute and chronic pain states. Drugs 1993;46:
1. Moore PA, Gage TW, Hersh EV, Yagiela JA, Haas DA. Adverse 313-40.
drug interactions in dental practice: professional and educational 30. Garrido MJ, Sayar O, Segura C, et al. Pharmacokinetic/
implications. JADA 1999;130:47-54. pharmacodynamic modeling of the antinociceptive effects of
2. Michalets EL. Update: clinically significant cytochrome P-450 drug (+)-tramadol in the rat: role of cytochrome P450 2D activity. J Phar-
interactions. Pharmacotherapy 1998;18:84-112. macol Exp Ther 2003;305:710-8.
3. Cupp MJ, Tracy TS. Cytochrome P450: new nomenclature and clin- 31. Orlando R, Piccoli P, De Martin S, Padrini R, Palatini P. Effect of
ical implications. Am Fam Physician 1998;57:107-16. the CYP3A4 inhibitor erythromycin on the pharmacokinetics of ligno-
4. Venkatakrishnan K, von Moltke LL, Greenblatt DJ. Effects of the caine and its pharmacologically active metabolites in subjects with
antifungal agents on oxidative drug metabolism: clinical relevance. normal and impaired liver function. Br J Clin Pharmacol 2003;55:
Clin Pharmacokinet 2000;38:111-80. 86-93.
5. Indiana University, School of Medicine, Division of Clinical Phar- 32. Hiroi T, Ohishi N, Imaoka S, Yabusaki Y, Fukui H, Funae Y.
macology. Cytochrome P450 drug interaction table. Available at: Mepyramine, a histamine H1 receptor antagonist, inhibits the
“medicine.iupui.edu/flockhart/table.htm”. Accessed Aug. 23, 2003. metabolic activity of rat and human P450 2D forms. J Pharmacol Exp
6. Antoniou T, Tseng AL. Interactions between recreational drugs Ther 1995;272:939-44.
and antiretroviral agents. Ann Pharmacother 2002;36:1596-613. 33. Hersh EV, Helpin ML, Evans OB. Local anesthetic mortality:
7. Piscitelli SC, Burstein AH, Chaitt D, Alfaro RM, Falloon J. Indi- report of case. ASDC J Dent Child 1991;58:489-91.
navir concentrations and St. John’s wort. Lancet 2000;355(9203):547-8. 34. Moore PA. Preventing local anesthesia toxicity. JADA
8. Dresser GK, Spence JD, Bailey DG. Pharmacokinetic- 1992;123:60-4.
pharmacodynamic consequences and clinical relevance of cytochrome 35. Cooper SA. New peripherally-acting analgesic agents. Annu Rev
P450 3A4 inhibition. Clin Pharmacokinet 2000;38:41-57. Pharmacol Toxicol 1983;23:617-37.
9. Bailey DG, Malcolm J, Arnold O, Spence JD. Grapefruit juice-drug 36. Hersh EV, Moore PA, Ross GL. Over-the-counter analgesics and
interactions. Br J Clin Pharmacol 1998;46:101-10. antipyretics: a critical assessment. Clin Ther 2000;22:500-48.
10. Bjornsson TD, Callaghan JT, Einolf HJ, et al. The conduct of in 37. Kirchheiner J, Meineke I, Freytag G, Meisel C, Roots I, Brock-
vitro and in vivo drug-drug interaction studies: a PhRMA perspective. J moller J. Enantiospecific effects of cytochrome P450 2C9 amino acid
Clin Pharmacol 2003;43:443-69. variants on ibuprofen pharmacokinetics and on the inhibition of
11. Bailey DG, Dresser GK, Bend JR. Bergamottin, lime juice, and cyclooxygenases 1 and 2. Clin Pharmacol Ther 2002;72:62-75.
red wine as inhibitors of cytochrome P450 3A4 activity: comparison 38. Brenner SS, Herrlinger C, Dilger K, et al. Influence of age and
with grapefruit juice. Clin Pharmacol Ther 2003;73:529-37. cytochrome P450 2C9 genotype on the steady-state disposition of
12. Bailey DG, Spence JD, Munoz C, Arnold JM. Interaction of citrus diclofenac and celecoxib. Clin Pharmacokinet 2003;42:283-92.
juices with felodipine and nifedipine. Lancet 1991;337(8736):268-9. 39. Kirchheiner J, Meineke I, Steinbach N, Meisel C, Roots I, Brock-
13. Lown KS, Bailey DG, Fontana RJ, et al. Grapefruit juice moller J. Pharmacokinetics of diclofenac and inhibition of cyclooxyge-
increases felodipine oral availability in humans by decreasing nases 1 and 2: no relationship to the CYP2C9 genetic polymorphism in
intestinal CYP3A protein expression. J Clin Invest 1997;99:2545-53. humans. Br J Clin Pharmacol 2003;55:51-61.
14. Jackson DL, Johnson BS. Inhalation and enteral conscious seda- 40. Tracy TS, Marra C, Wrighton SA, Gonzalez FJ, Korzekwa KR.
tion for the adult dental patient. Dent Clin North Am 2002;46:781-802. Involvement of multiple cytochrome P450 isoforms in naproxen O-
15. Hersh EV. Adverse drug interactions in dental practice: interac- demethylation. Eur J Clin Pharmacol 1997;52:293-8.
tions involving antibiotics, part II of a series. JADA 1999;130:236-51. 41. Jones A. Over-the-counter analgesics: a toxicology perspective.
16. Moore PA. Adverse drug interactions in dental practice: interac- Am J Ther 2002;9:245-57.
tions associated with local anesthetics, sedatives and anxiolytics, part 42. The top 200 prescriptions for 2002 by number of U.S. prescriptions
IV of a series. JADA 1999;130:541-54. dispensed. Available at: “www.rxlist.com/top200.htm”. Accessed July 16,
17. Olkkola KT, Aranko K, Luurila H, et al. A potentially hazardous 2003.
interaction between erythromycin and midazolam. Clin Pharmacol 43. Prescott LF. Current status of issues concerning the safety of
Ther 1993;53:298-305. over-the-counter analgesics and nonsteroidal anti-inflammatory drugs.
18. Mattila MJ, Idanpaan-Heikkila JJ, Tornwall M, Vanakoski J. In: Rainsford KD, Powanda MC, eds. Safety and efficacy of non-
Oral single doses of erythromycin and roxithromycin may increase the prescription (OTC) analgesics and NSAIDs. Boston: Kluwer; 1998:1-9.
effects of midazolam on human performance. Pharmacol Toxicol 44. Rumack BH. Acetaminophen hepatotoxicity: the first 35 years. J
1993;73:180-5. Toxicol Clin Toxicol 2002;40:3-20.

JADA, Vol. 135, March 2004 309


Copyright ©2004 American Dental Association. All rights reserved.
C L I N I C A L PHARMACOLOGY

45. Rivera-Penera T, Gugig R, Davis J, et al. Outcome of 70. Slots J, Feik D, Rams TE. Prevalence and antimicrobial suscepti-
acetaminophen overdose in pediatric patients and factors contributing bility of Enterobacteriaceae, Pseudomonadaceae and Acinetobacter in
to hepatotoxicity. J Pediatr 1997;130:300-4. human periodontitis. Oral Microbiol Immunol 1990;5:149-54.
46. Haas DA. Adverse drug interactions in dental practice: interac- 71. Batty KT, Davis TM, Ilett KF, Dusci LJ, Langton SR. The effect
tions associated with analgesics, part III in a series. JADA of ciprofloxacin on theophylline pharmacokinetics in healthy subjects.
1999;130:397-407. Br J Clin Pharmacol 1995;39:305-11.
47. Friedlander AH, Marder SR, Pisegna JR, Yagiela JA. Alcohol 72. Wijnands WJ, Vree TB, van Herwaarden CL. The influence of
abuse and dependence: psychopathology, medical management and quinolone derivatives on theophylline clearance. Br J Clin Pharmacol
dental implications. JADA 2003;134:731-40. 1986;22:677-83.
48. Over-the-counter drug products containing analgesic/antipyretic 73. Raaska K, Neuvonen PJ. Ciprofloxacin increases serum clozapine
active ingredients for internal use; required alcohol warning; final rule; and N-desmethylclozapine: a study in patients with schizophrenia. Eur
compliance date. U.S. Food and Drug Administration, Department of J Clin Pharmacol 2000;56:585-9.
Health and Human Services. Fed Regist 1999;64(51):13066-7. 74. Markowitz JS, Gill HS, Devane CL, Mintzer JE. Fluroquinolone
49. Slattery JT, Nelson SD, Thummel KE. The complex interaction inhibition of clozapine metabolism. Am J Psychiatry 1997;153:881.
between ethanol and acetaminophen. Clin Pharmacol Ther 1996; 75. Perkins DO. Predictors of noncompliance in patients with
60:241-6. schizophrenia. J Clin Psychiatry 2002;63:1121-8.
50. Rumack BH, Peterson RG. Acetaminophen overdose: incidence, 76. Ciancio SG, van Winkelhoff AJ. Antibiotics in periodontal
diagnosis and management in 416 patients. Pediatrics 1978;62(5 pt 2 therapy. In: Newman MG, van Winkelhoff AJ, eds. Antibiotic and
supplement):898-903. antimicrobial use in dental practice. 2nd ed. Chicago: Quintessence;
51. Rumack BH, Peterson RC, Koch GG, Amara IA. Acetaminophen 2001:113-26.
overdose: 662 cases with evaluation of oral acetylcysteine treatment. 77. Baumgartner JC. Antibiotics in endodontic therapy. In: Newman
Arch Intern Med 1981;141(special issue 3):380-5. MG, van Winkelhoff AJ, eds. Antibiotic and antimicrobial use in dental
52. Lyons L, Studdiford JS, Sommaripa AM. Treatment of practice. 2nd ed. Chicago: Quintessence; 2001:143-55.
acetaminophen overdosage with N-acetylcysteine. N Engl J Med 78. Peterson LJ. Antibiotics for oral and maxillofacial infections. In:
1997;296:174-5. Newman MG, van Winkelhoff AJ, eds. Antibiotic and antimicrobial use

Downloaded from jada.ada.org on April 14, 2010


53. Dart RC, Kuffner EK, Rumack BH. Treatment of pain of fever in dental practice. 2nd ed. Chicago: Quintessence; 2001:157-73.
with paracetamol (acetaminophen) in the alcoholic patient: a systemic 79. Beikler T, Flemmig TF. Antimicrobials in implant dentistry. In:
review. Am J Ther 2000;7:123-34. Newman MG, van Winkelhoff AJ, eds. Antibiotic and antimicrobial use
54. U.S. Food and Drug Administration, Center for Drug Evaluation in dental practice. 2nd ed. Chicago: Quintessence; 2001:195-211.
and Research, Nonprescription Drugs Advisory Committee. Safety 80. Kazmier FJ. A significant interaction between metronidazole and
issues related to acetaminophen. Available at: “www.fda.gov/ohrms/ warfarin. Mayo Clin Proc 1976;51:782-4.
dockets/ac/02/transcripts/3882T1.htm”. Accessed July 20, 2003. 81. O’Reilly RA. The stereoselective interaction of warfarin and
55. Trummel CL. Antiinflammatory drugs. In: Yagiela JA, Neidle EA, metronidazole in man. N Eng J Med 1976;295:354-7.
Dowd FJ, eds. Pharmacology and therapeutics for dentistry. 4th ed. St. 82. Blyden GT, Scavone JM, Greenblatt DJ. Metronidazole impairs
Louis: Mosby; 1998:297-319. clearance of phenytoin but not of alprazolam or lorazepam. J Clin
56. Villikka K, Varis T, Backman JT, Neuvonen PJ, Kivisto KT. Pharmacol 1988;28:240-5.
Effect of methylprednisolone on CYP3A4-mediated drug metabolism in 83. Kapseals dilantin (extended phenytoin sodium capsules, USP).
vivo. Eur J Clin Pharmacol 2001;57:457-60. In: Physicians’ desk reference. 57th ed. Montvale, N.J.: Medical
57. McCune JS, Hawke RL, LeCluyse EL, et al. In vivo and in vitro Economics; 2003:2531-3.
induction of human cytochrome P4503A4 by dexamethasone. Clin 84. Montgomery EH. Antibacterial antibiotics. In: Yagiela JA, Neidle
Pharmacol Ther 2000;68:356-66. EA, Dowd FJ, eds. Pharmacology and therapeutics for dentistry. 4th
58. LaForce CF, Szefler SJ, Miller MF, Ebling W, Brenner M. Inhibi- ed. St. Louis: Mosby; 1998:496-533.
tion of methylprednisolone elimination in the presence of erythromycin 85. Montgomery EH. Antimicrobial agents in the prevention and
therapy. J Allergy Clin Immunol 1983;72:34-9. treatment of infection. In: Yagiela JA, Neidle EA, Dowd FJ, eds. Phar-
59. Fost DA, Leung DY, Martin RJ, Brown EE, Szefler SJ, Spahn JD. macology and therapeutics for dentistry. 4th ed. St. Louis: Mosby;
Inhibition of methylprednisolone elimination in the presence of clar- 1998:634-43.
ithromycin therapy. J Allergy Clin Immunol 1999;103:1031-5. 86. Honig P, Wortham D, Zamani K, Conner D, Cantilena L. Effect of
60. Glynn AM, Slaughter RL, Brass C, D’Ambrosio R, Jusko WJ. erythromycin, clarithromycin and azithromycin on pharmacokinetics of
Effects of ketoconazole on methylprednisolone pharmacokinetics and terfenadine. Clin Pharmacol Ther 1993;53:161.
cortisol secretion. Clin Pharmacol Ther 1986;39:654-9. 87. Matitila MJ, Vanakokski J, Idänpään-Heikkilä JJ. Azithromycin
61. Varis T, Kaukonen KM, Kivisto KT, Neuvonen PJ. Plasma con- does not alter the effects of oral midazolam on human performance.
centrations and effects of oral methylprednisolone are considerably Eur J Clin Pharmacol 1994;47:49-52.
increased by itraconazole. Clin Pharmacol Ther 1998;64:363-8. 88. Harris S, Hilligoss DM, Colangelo PM, Eller M, Okerholm R.
62. Booker BM, Magee MH, Blum RA, Lates CD, Jusko WJ. Pharma- Azithromycin and terfenadine: lack of drug interaction. Clin Pharmacol
cokinetic and pharmacodynamic interactions between diltiazem and Ther 1995;58:310-5.
methylprednisolone in healthy volunteers. Clin Pharmacol Ther 89. Sanz M, Herrera D. Individual drugs. In: Newman MG, van
2002;72:370-82. Winkelhoff AJ, eds. Antibiotic and antimicrobial use in dental practice.
63. Varis T, Backman JT, Kivisto KT, Neuvonen PJ. Diltiazem and 2nd ed. Chicago: Quintessence; 2001:33-52.
mibefradil increase the plasma concentrations and greatly enhance the 90. Honig PK, Woosley RL, Zamani K, Conner DP, Cantilena LR Jr.
adrenal-suppressant effect of oral methylprednisolone. Clin Pharmacol Changes in the pharmacokinetics and electrocardiographic pharmaco-
Ther 2000;67:215-21. dynamics of terfenadine with concomitant administration of ery-
64. Varis T, Kivisto KT, Neuvonen PJ. Grapefruit juice can increase thromycin. Clin Pharmacol Ther 1993;53:231-8.
the plasma concentrations of oral methylprednisolone. Eur J Clin Phar- 91. Biglin KE, Faraon MS, Constance TD, Leih-Lai M. Drug-induced
macol 2000;56:489-93. torsades de pointes: a possible interaction of terfenadine and ery-
65. Loeffler PM. Oral benzodiazepines and conscious sedation: a thromycin. Ann Pharmacother 1994;28:282.
review. J Oral Maxillofac Surg 1992;50:989-97. 92. Kivisto KT, Neuvonen PJ, Klotz U. Inhibition of terfenadine
66. Chan E, McLachlan A, O’Reilly R, Rowland M. Stereochemical metabolism: pharmacokinetic and pharmacodynamic consequences.
aspects of warfarin drug interactions: use of a combined Clin Pharmacokinet 1994;27:1-5.
pharmacokinetic-pharmacodynamic model. Clin Pharmacol Ther 1994; 93. Honig PK, Wortham DC, Zamani K, Conner DP, Mullin JC, Can-
56:286-94. tilena LR. Terfenadine-ketoconazole interaction: pharmacokinetic and
67. Wenzel RG, Sarvis CA. Do butalbital-containing products have a electrocardiographic consequences. JAMA 1993;269:1513-8.
role in the management of migraine? Pharmacotherapy 2002;22: 94. Honig PK, Wortham DC, Hull R, et al. Itraconazole affects single-
1029-35. dose terfenadine pharmacokinetics and cardiac repolarization pharma-
68. Muller HP, Holderrieth S, Burkhardt U, Hoffler U. In vitro codynamics. J Clin Pharmacol 1993;33:1201-6.
antimicrobial susceptibility of oral strains of Actinobacillus actino- 95. Goss JE, Ramo BW, Blake K. Torsades de pointes associated with
mycetemcomitans to seven antibiotics. J Clin Periodontol 2002;29: astemizole (Hismanal) therapy. Arch Intern Med 1993;153:2705.
736-42. 96. Lefebvre RA, Van Peer A, Woestenborghs R. Influence of itra-
69. Slots J. Selection of antimicrobial agents in periodontal therapy. J conazole on the pharmacokinetics and electrocardiographic effects of
Periodontal Res 2002;37:389-98. astemizole. Br J Clin Pharmacol 1997;43:319-22.

310 JADA, Vol. 135, March 2004


Copyright ©2004 American Dental Association. All rights reserved.
C L I N I C A L PHARMACOLOGY

97. Kyrmizakis DE, Chimona TS, Kanoupakis EM, Papadakis CE, Ther 1997;62:41-9.
Velegrakis GA, Helidonis ES. QT prolongation and torsades de pointes 117. Soltero L, Carbajal H, Rodriguez-Montalvo C, Valdes A. Coad-
associated with concurrent use of cisapride and erythromycin. Am J ministration of tacrolimus and ketoconazole in renal transplant recipi-
Otolaryngol 2002;23:303-7. ents: cost analysis and review of metabolic effects. Transplant Proc
98. Piquette RK. Torsades de pointes induced by cisapride/ 2003;35:1319-21.
clarithromycin interaction. Ann Pharmacother 1999;33:22-6. 118. Vasquez E, Pollak R, Benedetti E. Clotrimazole increases
99. van Haarst AD, van ’t Klooster GA, van Gerven JM, et al. The tacrolimus blood levels: a drug interaction in kidney transplant
influence of cisapride and clarithromycin on QT intervals in healthy patients. Clin Transplant. 2001;15:95-9.
volunteers. Clin Pharmacol Ther 1998;64:542-6. 119. Bussey HI, Knodel LC, Boyle DA. Warfarin-erythromycin inter-
100. Desta Z, Kerbusch T, Flockhart DA. Effect of clarithromycin on action. Arch Intern Med 1985;145:1736-7.
the pharmacokinetics and pharmacodynamics of pimozide in healthy 120. Hassell D, Utt JK. Suspected interaction: warfarin and ery-
poor and extensive metabolizers of cytochrome P450 2D6 (CYP2D6). thromycin. South Med J 1985;78:1015-6.
Clin Pharmacol Ther 1999;65:10-20. 121. Bachmann K, Schwartz JI, Forney R Jr, Frogameni A, Jauregui
101. Spach DH, Bauwens JE, Clark CD, Burke WG. Rhabdomyolysis LE. The effect of erythromycin on the disposition kinetics of warfarin.
associated with lovastatin and erythromycin use. West J Med Pharmacology 1984;28:171-6.
1991;154:213-5. 122. Recker MW, Kier KL. Potential interaction between clar-
102. Kantola T, Kivisto KT, Neuvonen PJ. Erythromycin and vera- ithromycin and warfarin. Ann Pharmacother 1997;31:996-8.
pamil considerably increase serum simvastatin and simvastatin acid 123. Oberg KC. Delayed elevation of international normalized ratio
concentrations. Clin Pharmacol Ther 1998;64:177-82. with concurrent clarithromycin and warfarin therapy. Pharma-
103. Lees RS, Lees AM. Rhabdomyolysis from the coadminsistration cotherapy 1998;18:386-91.
of lovastatin and the antifungal agent itraconazole. N Engl J Med 124. Black DJ, Kunze KL, Wienkers LC, et al. Warfarin-fluconazole,
1995;333:664-5. part II: a metabolically based drug interaction: in vivo studies. Drug
104. Neuvonen PJ, Jalava KM. Itraconazole drastically increases Metab Dispos 1996;24:422-8.
plasma concentrations of lovastatin and lovastatic acid. Clin Pharmacol 125. Berrettini WH. A case of erythromycin-induced carbamazepine
Ther 1996;60:54-61. toxicity. J Clin Psychiatry 1986;47:147.

Downloaded from jada.ada.org on April 14, 2010


105. Neuvonen PJ, Kantola T, Kivisto KT. Simvastatin but not 126. Albani F, Riva R, Baruzzi A. Clarithromycin-carbamazepine
pravastatin is very susceptible to interaction with the CYP3A4 interaction: a case report. Epilepsia 1993;34:161-2.
inhibitor itraconazole. Clin Pharmacol Ther 1998;63:332-41. 127. O’Connor NK, Fris J. Clarithromycin-carbamazepine interaction
106. Mazzu AL, Lasseter KC, Shamblen EC, Agarwal V, Lettieri J, in a clinical setting. J Am Board Fam Pract 1994;7:489-92.
Sundaresen P. Itraconazole alters the pharmacokinetics of atorvastatin 128. Wong YY Ludden TM, Bell RD. Effect of erythromycin on carba-
to a greater extent than either cerivastatin or pravastatin. Clin Phar- mazepine kinetics. Clin Pharmacol Ther 1983;33:460-4.
macol Ther 2000;68:391-400. 129. Miles MV, Tennison MB. Erythromycin effects on multiple-dose
107. Bennett JC, Moreland LW. Musculoskeletal and connective carbamazepine kinetics. Ther Drug Monit 1989;11:47-52.
tissue disease. In: Cecil RL, Andreoli TE, eds. Cecil essentials of 130. Spina E, Arena D, Scordo MG, Fazio A, Pisani F, Perucca E. Ele-
medicine. 4th ed. Philadelphia: Saunders; 1997:921-7. vation of plasma carbamazepine concentrations by ketoconazole in
108. Shaukat A, Benekli M, Vladutiu GD, Slack JL, Wetzler M, Baer patients with epilepsy. Ther Drug Monit 1997;19:535-8.
MR. Simvastatin-fluconazole causing rhabdomyolysis. Ann Pharma- 131. Nair DR, Morris HH. Potential fluconazole-induced carba-
cother 2003;37:1032-5. mazepine toxicity. Ann Pharmacother 1999;33:790-2.
109. Liedholm H, Nordin G. Erythromycin-felodipine interaction. 132. Finch CK, Green CA, Self TH. Fluconazole-carbamazepine inter-
DICP 1991;25:1007-8. action. South Med J 2002;95:1099-100.
110. Neuvonen PJ, Suhonen R. Itraconazole interacts with felodipine. 133. Tenenbein M. Theophylline toxicity due to drug interaction. J
J Am Acad Dermatol 1995;33:134-5. Emerg Med 1989;7:249-51.
111. Tailor SA, Gupta AK, Walker SE, Shear NH. Peripheral edema 134. Paulsen O, Hoglund P, Nilsson LG, Bengtsson HI. The interac-
due to nifedipine-itraconazole interaction: a case report. Arch Dermatol tion of erythromycin with theophylline. Eur J Clin Pharmacol
1996;132:350-2. 1987;32:493-8.
112. Jensen CW, Flechner SM, Van Buren CT, et al. Exacerbation of 135. Wiggins J, Arbab O, Ayres JG, Skinner C. Elevated serum theo-
cyclosporine toxicity by concomitant administration of erythromycin. phylline concentration following cessation of erythromycin treatment.
Transplantation 1987;43:263-70. Eur J Respir Dis 1986;68:298-300.
113. Spicer ST, Liddle C, Chapman JR, et al. The mechanism of 136. Richards W, Church JA, Brent DK. Theophylline-associated
cyclosporine toxicity induced by clarithromycin. Br J Clin Pharmacol seizures in children. Ann Allergy 1985;54:276-9.
1997;43:194-6. 137. Iliopoulou A, Aldhous ME, Johnston A, Turner P. Pharmacoki-
114. Lampen A, Christians U, Guengerich FP, et al. Metabolism of netic interaction between theophylline and erythromycin. Br J Clin
the immunosuppressant tacrolimus in the small intestine: cytochrome Pharmacol 1982;14:495-9.
P450, drug interactions, and interindividual variability. Drug Metab 138. Tjia JF, Colbert J, Back DJ. Theophylline metabolism in human
Dispos 1995;23:1315-24. liver microsomes: inhibition studies. J Pharmacol Exp Ther
115. Gomez DY, Wacher VJ, Tomlanovich SJ, Hebert MF, Benet LZ. 1996;276:912-7.
The effects of ketoconazole on the intestinal metabolism and bioavail- 139. Fleischmann J. Topical and systemic antifungal and antiviral
ability of cyclosporine. Clin Pharmacol Ther 1995;58:15-9. agents. In: Newman MG, van Winkelhoff AJ, eds. Antibiotic and
116. Floren LC, Bekersky I, Benet LZ, et al. Tacrolimus oral bioavail- antimicrobial use in dental practice. 2nd ed. Chicago: Quintessence;
ability doubles with coadministration of ketoconazole. Clin Pharmacol 2001:69-88.

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