UNIT 2

PHARMACOKINETICS
COMPARTMENT MODELING

S.SANGEETHA., M.PHARM., (Ph.d)

DepartmentofPharmaceutics
SRMCollegeofPharmacy
SRMUniversity
1
 OVERVIEW

Basicconsiderationsinpharmacokinetics
Compartmentmodels
Onecompartmentmodel
Assumptions
Intravenousbolusadministration
Intravenousinfusion
Extravascularadministration(zeroorderandfirst
orderabsorptionmodel)
References

2
 BASICCONSIDERATIONS
INPHARMACOKINETICS
Pharmacokineticparameters
Pharmacodynamicparameters
Zeroorderkinetic
Firstorderkinetic
Mixedorderkinetic
Compartmentmodel
Noncompartmentmodel
Physiologicmodel

3
 Pharmacokineticmodels
Means of expressing mathematically or quantitatively, time
course of drug through out the body and compute meaningful
pharmacokinetic parameters.

Useful in :
Characterize the behavior of drug in patient.
Predicting conc. of drug in various body fluids with dosage
regimen.
Calculating optimum dosage regimen for individual patient.
Evaluating bioequivalence between different formulation.
Explaining drug interaction.

4
Compartmentmodels

5
 OBJECTIVE
To understand the assumptions associated with the one
compartment model

To understand the properties of first order kinetics and linear

models

To write the differential equations for a simple pharmacokinetic

model

To derive and use the integrated equations for a one compartment

linear model

To define, use, and calculate the parameters, Kel (elimination rate

constant), t1/2 (halflife), Cl (clearance), V (apparent volume of
distribution), and AUC (area under the concentration versus time
curve) as they apply to a one compartment linear model

6
 OPENandCLOSEDmodels:

The term open itself mean that, the

administered drug dose is removed from body
by an excretory mechanism ( for most drugs,
organs of excretion of drug is kidney)

If the drug is not removed from the body then

model refers as closed model.

7
OneCompartment

8
 PHARMACOKINETICS

Pharmacokinetics is the study of drug and/or

metabolite kinetics in the body.

The body is a very complex system and a drug

undergoes many steps as it is being absorbed,
distributed through the body, metabolized or
excreted (ADME).

9
10
 Assumptions

1. One compartment
Thedrug in the blood is in rapid equilibrium with
drug in the extravascular tissues.

Thisis not an exact representation however it is

useful for a number of drugs to a reasonable
approximation.

11
2. Rapid Mixing
We also need to assume that the drug is mixed
instantaneously in blood or plasma.

3. Linear Model
We will assume that drug elimination follows first
order kinetics.

12
 LinearModel FirstOrderKinetics

Firstorderkinetics

13
 Thisbehaviorcanbeexpressedmathematicallyas:

14
 Onecompartmentmodel

Onecompartmentmodelcanbedefined:

Onecom.openmodel i.v.bolus.

Onecom.openmodel cont.intravenousinfusion.

Onecom.openmodel extravas.administration
(zeroorderabsorption)

Onecom.openmodel extravas.Administration
(firstorderabsorption)

15
OneCompartmentModel,
Intravenous(IV)Bolus
Administration

16
 Rateofdrugpresentationtobodyis:

dx=ratein(availability) rateout(elimination)
dt

Sincerateinorabsorptionisabsent,equation
becomes
dx= rateout
dt

Ifrateoutoreliminationfollowsfirstorderkinetic

dx/dt=kEX(eq.1)

17
 Eliminationphase:

Eliminationphasehasthreeparameters:

Eliminationrateconstant

Eliminationhalflife

Clearance

18
 Eliminationrateconstant

Integrationofequation(1)

lnX=lnXo KE t(eq.2)

Xo=amtofdruginjectedattimet=zeroi.e.initial
amountofdruginjected
X=XoeK t E (eq.3)

logX=logXo KE t
2.303(eq.4)

19
 Sinceitisdifficulttodirectlydetermineamountof
druginbodyX,weuserelationshipthatexists
betweendrugconc.inplasmaCandX;thus

X=VdC(eq.5)

Soequation8becomes
logC=logCo KE t
2.303(eq.6)

25 20
 KE =Ke+Km+Kb+Kl+..(eq.7)
KE isoveralleliminationrateconstant

25 21
 Eliminationhalflife

t1/2 =0.693
KE (eq.8)
Eliminationhalflifecanbereadilyobtainedfromthe
graphoflogCversust

Halflifeisasecondaryparameterthatdependsupon
theprimaryparameterssuchasclearanceand
volumeofdistribution.

t1/2 =0.693Vd
ClT (eq.9)

22
 Apparentvolumeofdistribution

Definedasvolumeoffluidinwhichdrugappearstobe
distributed.
Vd=amountofdruginthebody=X
plasmadrugconcentrationC(eq.10)

Vd=Xo/Co
=i.v.bolusdose/Co (eq.11)

E.g.30mgi.v.bolus,plasmaconc.=0.732mcg/ml.
Vol.ofdist.=30mg/0.732mcg/ml
=30000mcg/0.732mcg/ml
=41liter.
23
 Fordrugsgivenasi.v.bolus,
Vd (area)=Xo/KE.AUC
.12.a

Fordrugsadmins.Extra.Vas.

Vd (area)=FXo/KE.AUC
..12.b
24
 Clearance
Clearance=rateofelimination
plasmadrugconc..
OrCl=dx/dt
C(eq.13)
Thus
Renalclearance= rateofeliminationbykidney
C
Hepaticclearance= rateofeliminationbyliver
C
Otherorganclearance=rateofeliminationbyorgan
C
Totalbodyclearance:
ClT =ClR +ClH +Clother (eq.14)

25 KLECOP, 25
 Accordingtoearlierdefinition
Cl=dx/dt
C
Submittingeq.1dx/dt=KE X,aboveeq.becomes
ClT =KE X/C (eq15)
Byincorporatingequation1andequationforvol.ofdist.(
Vd=X/C)Wecanget
ClT =KE Vd(eq.16)

25 KLECOP, 26
 Parallelequationscanbewrittenforrenaland
hepaticclearance.
ClH =KmVd(eq.17)
ClR =KeVd(eq.18)
butKE=0.693/t1/2
so,ClT=0.693Vd (eq.19)
t1/2

27
 Fornoncompartmentalmethodwhichfollowsone
compartmentalkineticis:
Fordruggivenbyi.v.bolus
ClT=Xo..20.a
AUC
Fordrugadministeredbye.v.
ClT=FXo..20.b
AUC
Fordruggivenbyi.v.bolus
renalclearance=Xu (eq.21)
AUC

28
 Organclearance

Rateofeliminationbyorgan=rateofpresentationtothe
organ rateofexitfrom
theorgan.

Rateofelimination=Q.Cin Q.Cout
(rateofextraction)=Q(Cin Cout)
Clorgan=rateofextraction/Cin
=Q(CinCout)/Cin
=Q.ER.(eq22)
Extractionratio:
ER=(Cin Cout)/Cin
ERisanindexofhowefficientlytheeliminatingorganclear
thebloodflowingthroughitofdrug.

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 According to ER, drugs can be classified as
Drugs with high ER (above 0.7)
Drugs with intermediate ER (between 0.70.3)
Drugs with low ER (below 0.3)
The fraction of drug that escapes removal by
organ is expressed as
F= 1 ER
where F= systemic availability when the
eliminating organ is liver.

30
 Hepaticclearance

ClH =ClT ClR

o Canalsobewrittendownfromeq22
o ClH=QH ERH
o QH=hepaticbloodflow.ERH=hepaticextractionratio.
o Hepaticclearanceofdrugcanbedividedintotwo
groups:
1. Drugswithhepaticbloodflowratelimitedclearance
2. Drugswithintrinsiccapacity limitedclearance

31
 Hepaticbloodflow

F=1-ERH
= AUCoral
AUC i.v

32
 Intrinsiccapacityclearance

Denoted as Clint, it is defined as the inherent ability of

an organ to irreversibly remove a drug in the absence
of any flow limitation.

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 Onecompartmentopenmodel:
Intravenousinfusion
Model can be represent as : ( i.v infusion)

Drug R0 Blood & other KE

Zero order Body tissues
Infusion
rate

dX/dt=Ro-KEX eq 23
X=Ro/KE(1-e-KEt) eq 24
Since X=VdC
C=Ro/KEVd(1-e-KEt) eq 25
=Ro/ClT(1-e-KEt) eq 26

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 At steady state. The rate of change of amount of drug
in the body is zero ,eq 23 becomes
Zero=Ro-KEXSS 27
KEXSS=Ro 28
CSS=Ro/KEVd 29
=Ro/ClT i.e infusion rate ....30
clearance
Substituting eq. 30 in eq. 26
C=CSS(1-e-KEt) 31
Rearrangement yields:
[CSS-C]=e-KEt . ...32
CSS
log CSS-C = -KEt 33
CSS 2.303
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 If n is the no. of half lives passed since the start of
infusion(t/t1/2)
Eq. can be written as
C=CSS [1-(1/2)n] 34

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 Infusionplusloadingdose

Xo,L=CSSVd35
SubstitutionofCSS=Ro/KEVd
Xo,L=Ro/KE36
C=Xo,L/Vd eKEt+Ro/KEVd(1eKEt)37

37
 Assessment of
pharmacokinetic
parameter
AUC=Ro T/KE Vd
=Ro T/ClT
=CSS T
WhereT=infusiontime

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 One compartment open model :
extra vascular administration
When drug administered by extra vascular route (e.g.
oral, i.m, rectal ), absorption is prerequisite for its
therapeutic activity.

39
 dX/dt=rate of absorption-rate of elimination
dX /dt = dXev/dt dXE/dt 38

dXev/dt >dXE/dt

dXev/dt=dXE/dt

dXev/dt<dXE/dt

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 Onecompartmentmodel:extravascularadmin(zero
orderabsorption)
Thismodelissimilartothatforconstantrate
infusion.
R0 Blood & other
Drugatsite Elimination
Body tissues
zeroorder
absorption
o RateofdrugabsorptionasincaseofCDDS,is
constantandcontinuesuntiltheamountofdrugat
theabsorptionsite(e.g.GIT)isdepleted.
o Allequationsforplasmadrugconc.profilefor
constantratei.v.infusionarealsoapplicabletothis
model.

41
 Onecompartmentmodel:extravascular
admin(firstorderabsorption)

Drugthatentersthebodybyfirstorderabsorption
processgetsdistributedinthebodyaccordingtoone
compartmentkineticandiseliminatedbyfirstorder
process.
Themodelcanbedepictedasfollows:

Ka Blood & other

KE
elimination
Drugatsite First order Body tissues
absorption

42
 Thedifferentialformifeq.38is
dX/ dt=ka Xa-KEX 39

X=Ka FXo /Ka-KE [e -KEt-e-Kat] 40

C=Ka F Xo/Vd (Ka-KE) [e -KEt-e-Kat] 41

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Multi CompartmentModels

44
 Contents

Introduction
Multi Compartmentmodels
TwoCompartmentOpenmodel
Intravenousbolusadministration
Extravascularadministration
References

45
 Ideallyatruepharmacokineticmodelshould
betheonewitharateconstantforeachtissue
undergoingequilibrium.
Thereforebestapproachistopooltogether
tissuesonthebasisofsimilarityintheir
distributioncharacteristics.
Thedrugdispositionoccursbyfirstorder.
Multicompartmentcharacteristicsarebest
describedbyadministrationasi.v.bolusand
observingthemannerinwhichtheplasma
concdeclineswithtime.
46
 Multicompartmentmodels
(Delayeddistributionmodels)
Onecompartmentisdescribedbymono
exponentialtermi.e.elimination.
Forlargeclassofdrugsthistermsisnot
sufficienttodescribeitsdisposition.
Itneedsabi ormulti exponentialterms.
Thisisbecausethebodyiscomposedofa
heterogeneousgroupoftissueseachwith
differentdegreeofbloodflowandaffinityfor
drugandthereforedifferentratesof
elimination.
47
 Theno.ofexponentialsrequiredtodescribesucha
plasmaleveltimeprofiledeterminestheno.of
kineticallyhomogeneouscompartmentsintowhich
adrugwilldistribute.
Thesimplestandcommonestisthetwo
compartmentmodelwhichclassifiesthebody
tissuesintwocategories:
1. CentralcompartmentorCompartment1
2. PeripheralorTissueCompartmentor
Compartment2.

48
 Compartment1comprisesofbloodandhighly
perfusedtissueslikeliver,lungs,kidneys,etc.
thatequilibriatewiththebodyrapidly.
Eliminationusuallyoccursfromthis
compartment.
Compartment2comprisesofpoorlyperfused
andslowequilibriatingtissuessuchas
muscles,skin,adipose,etc.
Consideredasahybridofseveralfunctional
physiologicunits.

49
 Dependinguponthecompartmentfromwhichthe
drugiseliminated,the2compartmentmodelcanbe
furthercategorisedinto:

WitheliminationfromCentralcompartment
Witheliminationfromperipheralcompartment
Witheliminationfromboththecompartments
Intheabsenceofinformation,eliminationisassumed
tooccurexclusivelyfromthecentralcompartment.

50
 TwocompartmentOpenmodelivbolus
administration:
Eliminationfromcentralcompartment
Fig

1 2

Central peripheral

Aftertheivbolusofadrugthedeclineintheplasma
conc.isbiexponential.
Twodispositionprocesses distributionand
elimination.
51
 Thesetwoprocessesareonlyevidentwhena
semilogplotofCvstismade.
Initially,theconc.ofdruginthecentralcompartment
declinesrapidly,duetothedistributionofdrugfrom
thecentralcompartmenttotheperipheral
compartment.ThisiscalledDistributivephase.
Apseudodistributionequilibriumoccursbetween
thetwocompartmentsfollowingwhichthe
subsequentlossofdrugfromthecentral
compartmentisslowandmainlyduetoelimination.

52
 Thissecond,slowerrateprocess,iscalledas
thepostdistributiveoreliminationphase.
Incontrasttothiscompartment,theconcof
drugintheperipheralcompartmentfirst
increasesandreachesitsmax.
Followingpeak,thedrugconcdeclineswhich
correspondstothepostdistributivephase.
dCc=K21 Cp K12 Cc KE Cc
dt

53
ExtendingtherelationshipX=Vd C
dCc=K21 Xp K12 Xc KE Xc
dtVp Vc Vc
X=amt.ofdruginthebodyatanytimet
remainingtobeeliminated
C=drugconcinplasma
Vd=proportionalityconstapp.volumeof
distribution
XcandXp=amtofdruginC1andC2
Vc andVp=apparentvolumesofC1andC2
54
 Therateofchangeindrugconcinthe
peripheralcomponentisgivenby:
dCp=K12 Cc K12 Cp
dt
=K12 Xc K21 Xp
Vc Vp
Onintegrationequationgivesconcofdrugin
centralandperipheralcompartmentsatany
giventimet:
Cc =Xo [(K21 a) eat+(K21 b) ebt]
b aa b
55
 [(K
Cp =Xo 21 a) eat +(K b)ebt]
12
Vc b aa b
Xo=ivbolusdose
aandb=hybridfirstorderconstantsforrapid
dissolutionphaseandsloweliminationphase,
whichdependentirelyon1st orderconstants
K12,K21,KE
TheconstantsK12,andK21 thatdepictthe
reversibletransferofdrugbetweenthe
compartmentsarecalledmicroortransfer
constants.

56
 Therelationbetweenhybridand
microconstantsisgivenas:
a+b=K12 +K21 +KE
ab=K21 KE

Cc =Aeat +Bebt

Cc=distributionexponent+elimination
exponent
AandBarehybridconstantsfortwoexponents
andcanberesolvedbygraphbymethodof
residuals.
57
 [
A=X0 K21 a ] [
=Co K21 a ]
Vc b ab a

[
B=X0 K21 b ] =C [K
o 21 b ]
Vc a ba b

Co=plasmadrugconcimmediatelyafteri.v.
injection

58
 Methodofresiduals:thebiexponential
dispositioncurveobtainedafteri.v.bolusofa
drugthatfitstwocompartmentmodelcanbe
resolvedintoitsindividualexponentsbythe
methodofresiduals.
C=Aeat+Bebt
Fromgraphtheinitialdeclineduetodistributionis
morerapidthantheterminaldeclinedueto
eliminationi.e.therateconstanta>>band
hencethetermeat approacheszeromuchfaster
thanebt
C=Bebt
logC=logB bt/2.303C=backextrapolated
pl.conc

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 AsemilogplotofCvstyieldstheterminallinear
phaseofthecurvehavingslopeb/2.303andwhen
backextrapolatedtotimezero,yieldsyinterceptlog
B.Thet1/2fortheeliminationphasecanbeobtained
fromequationt1/2=0.693/b.
Residualconcvaluescanbefoundas
Cr =C C=Aeat
logCr=logA at
2.303
AsemilogplotCrvstgivesastraightline.

60
C0=A+B

KE =abc
Ab+Ba

K12 =AB(b a)2

C0(Ab+Ba)

K21 =Ab+Ba
C0
61
 Fortwocompartmentmodel,KEistherate
constantforeliminationofdrugfromthe
centralcompartmentandbistherate
constantforeliminationfromtheentire
body.Overalleliminationt1/2canbe
calculatedfromb.

AreaUnder(AUC)=A +B
theCurveab
App.volumeofCentral=X0 =X0
compartmentC0 KE (AUC)
62
App.volumeof=VP =VC K12
PeripheralcompartmentK21
Apparentvolumeofdistributionatsteadystate
orequilibrium
Vd,ss =VC+VP
Vd,area = X0
bAUC
TotalsystemicClearence=ClT =bVd
RenalClearence=ClR=dXU=KEVC
dt

63
 TherateofexcretionofUnchangeddrugin
urinecanberepresentedby:
dXU =KE Aeat+KE Bebt
dt
Theaboveequationcanberesolvedinto
individualexponentsbythemethodof
Residuals.

64
 Two Compartmentopenmodel
I.V.Infusion
1 2
Central Peripheral

Theplasmaorcentralcompartmentconcofa
drugwhenadministeredasconstantrate(0
order)i.v.infusionisgivenas:

C= R0 [1+(KE b)eat+(KE a)ebt]

VC KE b aa b

65
Atsteadystate(i.e.attimeinfinity)the
secondandthethirdterminthebracket
becomeszeroandtheequationreduces
to:
Css = R0
VCKE
NowVCKE=Vd b
CSS=R0 =R0
Vdb ClT
TheloadingdoseX0,L =Css Vc =R0
KE
66
 TwoCompartmentOpenModel
Extravascularadministration
First OrderAbsorption:
Themodelcanbedepictedasfollows:

2
1
Central peripheral

67
Foradrugthatentersthebodybyafirstorder
absorptionprocessanddistributedaccordingtotwo
compartmentmodel,therateofchangeindrugconc
inthecentralcompartmentisdescribedbythree
exponents:
Anabsorptionexponent,andthetwousualexponents
thatdescribedrugdisposition.
Theplasmaconcatanytimetis
C=Nekat +Leat +Mebt
C=Absorption+Distribution+Elimination
exponentexponentexponent

68
Besidesthemethodofresiduals,Kacanalsobefound
byLooRiegelmanmethodfordrugthatfollowstwo
compartmentcharacteristics.
Thismethodrequiresplasmadrugconcentration time
databothafteroralandi.v.administrationofthe
drugtothesamesubjectatdifferenttimesinorder
toobtainallthenecessarykineticconstants.
Despiteitscomplexity,themethodcanbeappliedto
drugsthatdistributeinanynumberof
compartments.

69
 Threecompartmentmodelandapplicationsof
pharmacokineticparametersindosagedevelopment

70
 THREECOMPARTMENTMODEL
Gibaldi&Feldmandescribedathreecompartmentopen
modeltoexplaintheinfluenceofrouteofadministration.i.e.
intravenousvs.oral,ontheareaundertheplasma
concentrationvs.timecurve.
Portmanutilizedathreecompartmentmodelwhichincluded
metabolism&excretionofhydroxynalidixicacid.

71
 DRUG INPUT

DEEP
CENTRAL TISSUE TISSUE
COMPARTMENT COMPARTMENT COMPARTMENT

K10

THREE COMPARTMENT CATENARY MODEL

RAPID IV
DRUG INPUT

K21 K13
DEEP
TISSUE CENTRAL
TISSUE
COMPARTMENT COMPARTMENT
COMPARTMENT
K31
K12
DRUG OUTPUT K10

THREE COMPARTMENT MAMMILLARY MODEL

72
 Threecompartmentmodelconsistofthefollowing
compartments.
9 Centralcompartment.
9 Tissuecompartment.
9 Deeptissuecompartment.

Inthiscompartmentmodeldrugdistributesmostrapidlyinto
firstorcentralcompartment.
Lessrapidlyintosecondortissuecompartment.
Veryslowlytothethirdordeeptissuecompartment.Thethird
compartmentispoorintissuesuchasbone&fat.

73
 Eachcompartmentindependentlyconnectedtothecentral
compartment.
Notarireportedthetriexponentialequation
C=Aet+Bet+Cet
A,B,CaretheyInterceptofextrapolatedlines.
,, aretherateconstants.

74
 RAPIDI.VBOLUSADMINISTRATIONS
Whenthedrugisadministeredbyi.vthedrugwillrapidly
distributedinc.c,lessrapidlyintot.c.veryslowlyintodeep
tissuecompartment.

PLASMAPROFILE
Whenthedrugisadministeredbyi.vtheplasmaconc.will
increasedinc.cthisisfirstorderrelease.
Theconc.ofdruginc.c.exhibitsaninitialdistributionthisis
veryrapid.
drugincentralcompartmentexhibitsaninitialdistributionthisisvery
rapid.

75
 PHARMACOKINETICPARAMETERS

BIOLOIGICALHALFLIFE

Itisdefinedasthetimetakenfortheamountofdruginthe
bodyaswellasplasmatodeclinebyonehalfor50%its
initialvalue.

Concentrationofdruginplasmaasafunctionoftimeis
C=Ae t+Be t+Ce t
Inthisequation>> sometimeafterthedistributive
phase(i.e.whentimebecomelarge)thetworighthandside
termsvaluesareequaltozero.

76
 Theeq..isconvertedinto
C=Aet
Takingthenaturallogarithmonbothsides
Therateconstantofthisstraightlineisandbiological
halflifeis
t1/2 =0.693/

77
 Volumeofcentralcompartment

Attime=0
C=Ae t+Be t+Ce t
Thisequationbecomes
CO =A+B+C1
CO =conc.ofplasmaimmediatelyafterthei.vadministration
Whenadministeredthedoseisnotdistributedintissue
compartment.
Thereforethedrugispresentinc.conly.
IfDisdoseadministeredthenCO =D/VC2
VC=volumeofdruginc.c

78
 Combiningthe1&2eq..
A+B+C=D/VC
or
VC =D/A+B+C=D/CO
VC =D/CO CO Conc.Ofdruginplasma
ELIMINATIONRATECONSTANT
Drug that follows three compartment kinetics and administered by
i.v injection the decline in the plasma drug conc. is due to
elimination of drug from the three compartments.
KE=(A+B+C) /A +B +C
AREAUNDERCURVE:
AUC=A/+B/+C/

79
Applicationsofpharmacokinetics
Tounderstandprocessofabsorption,
distributionandeliminationafteradministrationofdrug,
Whichaffectsonsetandintensityofbiologicalresponse.
Toaccessdrugmoietyintermsofplasmadrugconc
responsewhichisnowconsideredasmoreappropriate
parameterthenintrinsicpharmacologicalactivity.
Indesignandutilizationofinvitromodelsystemthatcan
evaluatedissolutioncharacteristicsofnewcompound
formulatedasnewdrugformulationsandestablish
meaningfulinvivoinvitrocorrelationship.
Indesignanddevelopmentofnewdrugandtheir
appropriatedosageregimen .

80
 Insafeandeffectivemanagementofpatientsby
improvingdrugtherapy.

Tounderstandconceptofbioavailabilitywhichhas
beenusedbyregulatoryauthoritiestoevaluate
andmonitorinvivoperformanceofnewdosage
formsandgenericformulations.

Tocarryoutbioavailabilityandbioequivalence
studies.

Wecanusedpharmacokineticprinciplesinthe
developmentofN.D.D.Slikemicrospheresand
Nanoparticles .

e.g.Thedrugwithshorthalflifeabout26hcanbe
formulatedascontrolledreleasedrugsbyusing
polymers.
Thelowerbioavailabilityofthedrugscanbeincreasedby
usingseveralcomponents.
e.g. cyclodextrin
81
Roleofpharmacokineticsindrugdesign
Manydrugsareinvestigatednowadaystheestimationof
activityandpharmacokineticspropertiesareimportantfor
knowingtheADMEofthatparticulardrug.

Byunderstandingthemechanismofdiseasethedrugdesign
isdone.Thedrugdesignisbasedonthemechanismofthe
particulardisease.

Somenewlydiscovereddrugsthatshowsveryhighactivity
invitrobutininvivothatdrugnotshowshighactivityor
showinghightoxicactivity.

Thistoxicnatureofthedrugininvivowillbeexplainedby
studyingthepharmacokineticspropertiesandthetoxicity
mayresultfromtheformationofreactivemetabolites.

82
 Somenewlyinventeddrugsshowingundesirablep.k
propertiessuchastoolongortooshortt1/2 ,poorabsorption
andextensivefirstpassmetabolism.

ABSORPTION
Twophysicochemicalfactorsthateffectthebothextentand
rateofabsorptionarelipophilicityandsolubility.
Increaseinthelipophilicitynatureofdrugresultsincreasein
oralabsorption.
1. e.g.Biophosphonatesdrugwithpoorlipophilicitywillbe
poorlyabsorbedafteroraladministration.
2. absorptionofthebarbituratescompoundsincreasedwith
increasinglipophilicity.

83
 Higherthelipophilicityofadrugthehigheritspermeabilityandthegreaterits
metabolicclearanceduetofirstpasseffect.

Theeffectofthelipophilicityonmembranepermeabilityandfirstpassmetabolism
appeartohaveopposingeffectonthebioavailability.

Solubilityisalsoanimportantdeterminantindrugabsorption.

Vavccasuccessfullydevelopedanovelhydroxyethylenedipeptitideisostere&selective
HIVproteaseinhibitors.

HIVproteaseinhibitorsarebasicallylipophilicandpoorlysolubleresultinginpoor
bioavailability.

ThesolubilityoftheHIVproteaseinhibitorscanincreasedbyincorporatingabasic
amineintothebackboneofthisseries.

Prodrugsaredevelopedtoimproveoralabsorption.
Egpivampicillin,becampicillinaretheprodrugsofampicillin.

84
 Distribution

Lipophilicityofthedrugaffectsthedistributionthehigher
thelipophilicityofadrugthestrongeritsbindingto
protein&thegreateritsdistribution.
e.g.Thiopental&polychlorinatedinsecticides.
Thesedrugsarehighlydistributedandaccumulatein
adiposetissue.

85
 Plasmahalflife

Administrationofadrugwithashorthalfliferequires
frequentdosingandoftenresultsinasignificantinpatient
compliance.
Halflifedeterminedbydistribution&elimination
clearance.
Theprolongationofhalflifecanbeachievedbyincreasing
thevolumeofdistribution&decreasingtheclearance,
latterappeartobeeasiertomodifythechemicalstructure
toslowadrugclearancethantoincreaseitsvolumeof
distribution.

86
 E.g.Theadditionofanalkylaminesidechainlinkedtothe
dihydropyridine2methylgroupyieldamlodipinewithalower
clearancewhichhasanimprovedoralbioavailabilityandplasma
halflifewithoutlossofantihypertensiveactivity.

ROLEOFP.KINDRUGDEVELOPMENT

Invitrostudiesareveryusefulinstudyingthefactorsinfluencing
drugabsorptionandmetabolism.
Thesestudiesareusefulforthenewdrug
development.

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 Invitro studiesofdrugmetabolism
1. Determinationofmetabolicpathways
Studyofdrugmetabolicpathwaysareusefulfor
determiningthenatureofmetabolites.
Animalsspeciesusedfortoxicitystudies.
9 e.g.Themajormetabolicpathwaysofindinavirinhuman
havebeenidentificateas,
9 Glucaronidationatthepyridinenitrogentoyielda
quaternaryammoniumconjugate
9 Pyridinenoxidation
9 Parahydroxylationofthephenylmethylgroup
9 3hydroxylationofthechain
9 N depyridomethylation
Isolation&culturedhepatocytesalsousedoftenasinvitro
modelsforidentifyingmetabolicpathwaysofdrug.

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 IDENTIFICATIONOFDRUGMETABOLIZINGENZYMES

Metabolismofdrugsisusuallyverycomplex,involvingseveral
pathwaysandvariousenzymesystem.

Insomecasesallthemetabolicreactionsofadrugare
catalyzedbyasingleisozyme,whereasinothercasesasingle
metabolicreactionsmayinvolvemultipleisozymesordifferent
enzymesystem
1. Oxidativemetabolicreactionsofindinavirareallcatalyzedbya
singleisozymeinhumanlivermicrosomes.
2. Twoisozymescytp142&cytp344areinvolvedinhumanliver
microsomes.

Stearnsdemonstratedthatlosartanisconvertedtoitsactive
carboxylicacidmetaboliteinhumanlivermicrosomes.

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 INVITROSTUDIESOFPROTEINBINDING

Drugparticlesareabsorbedfromtheintestineandbond
withtheplasmaproteins.
Absorbedparticlesareintwoformsbound,unbound
Invitro Invivoproteinbinding:
Therearenumerousinvitromethodsforthe
determinationofproteinbindings.
e.g.Equilibriumdialysis.
Ultrafiltration.
Ultracentrifugation.
Equilibriumdialysismethodformeasuringtheunbound
phenytoinfractioninplasma.

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 Thesebindingofdrugtoplasmaproteinsisanimportantfactor
indeterminingtheirp.k&pharmacologicaleffects.
Microdialysishasbeendevelopedformeasuringtheunbound
drugconc.inbiologicalfluid.
Theuseofmicrodialysisistodeterminetheplasmaprotein
bindingofdrugs&evaluatedbycomparingwithultrafiltration
andequilibriumdialysis.

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 Plasmaandtissueproteinbinding

Itisgenerallybelivedthatonlytheunbounddrugcan
diffuseacrossmembranes.
Thereforedrugproteinbindinginplasmaandtissuescan
affectthedistributionofdrugsinthebody.
Kineticallythesimplestquantitativeexpressionrelating
thevolumeofdistributiontoplasmaandtissuebindingis
givenas
Vd=Vp+Vt fp /ft
VPPlasmavolume
VtTissuevolume
ft &fpfractionofunbounddrugintissue&plasma.

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 ThisrelationshiptellsthattheVdincreasewhenfpisincreased
anddecreasewhenftisincreased.
Severalmethodshavebeendevelopedforthestudyoftissue
binding.Theseincludeperfusedintactorganstissueslicesor
tissuehomogenates.
Inprinciplethesemethodsallowthedirectdeterminationof
tissuebindingbutrequiredremovaloftissuesfromthebody.

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 References:
Biopharmaceuticsandpharmacokinetics.
PLMadan,pageno.73105,1st edn.
Biopharmaceuticsandpharmacokinetics.
D.MBrahmankarandSunil.B.Jaiswal,pageno.212259,1st
edn
AppliedBiopharmaceuticsandpharmacokinetics
LeonshargelandAndrewYu,pageno.4762
4th edn.
BiopharmaceuticsandclinicalpharmacokineticsByMilo
Gibaldi,pageno.1423,4th edn.
www.books.google.com

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