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AppliedBiopharmaceutics&Pharmacokinetics>Chapter7.PharmacokineticsofOralAbsorption>

PHARMACOKINETICSOFDRUGABSORPTION
Thepharmacokineticsofdrugsfollowingintravenousdrugadministrationaremoresimpletomodel
comparedtoextravasculardelivery(seeChapters1,2,3,4,5,and6).Extravasculardeliveryroutes,
particularlyoraldosing,areimportantandpopularmeansofdrugadministration.Unlikeintravenous
administration,inwhichthedrugisinjecteddirectlyintotheplasma,pharmacokineticmodelsafter
extravasculardrugadministrationmustconsidersystemicdrugabsorptionfromthesiteofadministration,
eg,thelung,thegut,etc.,intotheplasma.Extravasculardrugdeliveryisfurthercomplicatedbyvariables
attheabsorptionsite,includingpossibledrugdegradationandsignificantinterandintrapatient
differencesintherateandextentofabsorption.Absorptionandmetabolicvariablesarecharacterized
usingpharmacokineticmethods.Thevariabilityinsystemicdrugabsorptioncanbeminimizedtosome
extentbyproperbiopharmaceuticaldesignofthedosageformtoprovidepredictableandreliabledrug
therapy(Chapters14,15,and16).Themajoradvantageofintravenousadministrationisthattherateand
extentofsystemicdruginputiscarefullycontrolled.
Thesystemicdrugabsorptionfromthegastrointestinal(GI)tractorfromanyotherextravascularsiteis
dependenton(1)thephysicochemicalpropertiesofthedrug,(2)thedosageformused,and(3)the
anatomyandphysiologyoftheabsorptionsite.Althoughthischapterwillfocusprimarilyonoraldosing,
theconceptsdiscussedheremaybeeasilyextrapolatedtootherextravascularroutes.Fororaldosing,
suchfactorsassurfaceareaoftheGItract,stomachemptyingrate,GImobility,andbloodflowtothe
absorptionsiteallaffecttherateandtheextentofdrugabsorption.Inpharmacokinetics,theoverallrate
ofdrugabsorptionmaybedescribedaseitherafirstorderorzeroorderinputprocess.Most
pharmacokineticmodelsassumefirstorderabsorptionunlessanassumptionofzeroorderabsorption
improvesthemodelsignificantlyorhasbeenverifiedexperimentally.
Therateofchangeintheamountofdruginthebody,dDB/dt,isdependentontherelativeratesofdrug
absorptionandelimination(Fig.71).Thenetrateofdrugaccumulationinthebodyatanytimeisequalto
therateofdrugabsorptionlesstherateofdrugelimination,regardlessofwhetherabsorptioniszeroorder
orfirstorder.

Figure71.

Page2 of28

Modelofdrugabsorptionandelimination.

WhereDGI isamountofdruginthegastrointestinaltractandDEisamountofdrugeliminated.Aplasma
leveltimecurveshowingdrugadsorptionandeliminationrateprocessesisgiveninFigure72.Duringthe
absorptionphaseofaplasmaleveltimecurve(Fig.72),therateofdrugabsorptionisgreaterthanthe
rateofdrugelimination.Notethatduringtheabsorptionphase,eliminationoccurswheneverdrugis
presentintheplasma,eventhoughabsorptionpredominates.

Figure72.

Plasmaleveltimecurveforadruggiveninasingleoraldose.Thedrugabsorptionandeliminationphasesofthe
curveareshown.

Atthepeakdrugconcentrationintheplasma(Fig.72)therateofdrugabsorptionjustequalstherateof
drugelimination,andthereisnonetchangeintheamountofdruginthebody.

Immediatelyafterthetimeofpeakdrugabsorption,somedrugmaystillbeattheabsorptionsite(ie,in
theGItractorothersiteofadministration).However,therateofdrugeliminationatthistimeisfaster

Page3 of28

thantherateofabsorption,asrepresentedbythepostabsorptionphaseinFigure72.

Whenthedrugattheabsorptionsitebecomesdepleted,therateofdrugabsorptionapproacheszero,or
dD GI/dt=0.Theplasmaleveltimecurve(nowtheeliminationphase)thenrepresentsonlythe
eliminationofdrugfromthebody,usuallyafirstorderprocess.Therefore,duringtheeliminationphase
therateofchangeintheamountofdruginthebodyisdescribedasafirstorderprocess,

wherekisthefirstordereliminationrateconstant.

ZEROORDERABSORPTIONMODEL
Zeroorderdrugabsorptionfromthedosingsiteintotheplasmausuallyoccurswheneitherthedrugis
absorbedbyasaturableprocessorazeroordercontrolledreleasedeliverysystemisused(seeChapter
17).ThepharmacokineticmodelassumingzeroorderabsorptionisdescribedinFigure73.Inthismodel,
druginthegastrointestinaltract,DGI,isabsorbedsystemicallyataconstantrate,k0.Drugis
simultaneouslyandimmediatelyeliminatedfromthebodybyafirstorderrateprocessdefinedbyafirst
orderrateconstant,k.Thismodelisanalogoustothatoftheadministrationofadrugbyintravenous
infusion(Chapter5).

Figure73.

Onecompartmentpharmacokineticmodelforzeroorderdrugabsorptionandfirstorderdrugelimination.

TherateoffirstordereliminationatanytimeisequaltoDBk.Therateofinputissimplyk0.Therefore,
thenetchangeperunittimeinthebodycanbeexpressedas

IntegrationofthisequationwithsubstitutionofVDCp forDB produces

Therateofdrugabsorptionisconstantuntiltheamountofdruginthegut,DGI,isdepleted.Thetimefor
completedrugabsorptiontooccurisequaltoDGI/k0.Afterthistime,thedrugisnolongeravailablefor

Page4 of28

absorptionfromthegut,andEquation7.7nolongerholds.Thedrugconcentrationintheplasma
subsequentlydeclinesinaccordancewithafirstordereliminationrateprocess.

FIRSTORDERABSORPTIONMODEL
Althoughzeroorderabsorptioncanoccur,absorptionisusuallyassumedtobeafirstorderprocess.This
modelassumesafirstorderinputacrossthegutwallandfirstordereliminationfromthebody(Fig.74).
Thismodelappliesmostlytotheoralabsorptionofdrugsinsolutionorrapidlydissolvingdosage
(immediaterelease)formssuchastablets,capsules,andsuppositories.Inaddition,drugsgivenby
intramuscularorsubcutaneousaqueousinjectionsmayalsobedescribedusingafirstorderprocess.

Figure74.

Onecompartmentpharmacokineticmodelforfirstorderdrugabsorptionandfirstorderelimination.

Inthecaseofadruggivenorally,thedosageformfirstdisintegratesifitisgivenasasolid,thenthedrug
dissolvesintothefluidsoftheGItract.Onlydruginsolutionisabsorbedintothebody.Therateof
disappearanceofdrugfromthegastrointestinaltractisdescribedby

whereka isthefirstorderabsorptionrateconstantfromtheGItract,Fisthefractionabsorbed,andDGI
istheamountofdruginsolutionintheGItractatanytimet.Integrationofthedifferentialequation(7.8)
gives

whereD0 isthedoseofthedrug.
TherateofdrugeliminationisdescribedbyafirstorderrateprocessformostdrugsandisequaltokDB.
Therateofdrugchangeinthebody,dD B/dt,isthereforetherateofdrugin,minustherateofdrugout
asgivenbythedifferentialequation,Equation7.10:

whereFisthefractionofdrugabsorbedsystemically.Sincethedruginthegastrointestinaltractalso
followsafirstorderdecline(ie,thedrugisabsorbedacrossthegastrointestinalwall),theamountofdrug

Page5 of28

inthegastrointestinaltractatanytimetisequaltoD0ekat.

ThevalueofFmayvaryfrom1forafullyabsorbeddrugto0foradrugthatiscompletelyunabsorbed.
Thisequationcanbeintegratedtogivethegeneraloralabsorptionequationforcalculationofthedrug
concentration(Cp)intheplasmaatanytimet,asshownbelow.

AtypicalplotoftheconcentrationofdruginthebodyafterasingleoraldoseispresentedinFigure75.

Figure75.

Typicalplasmaleveltimecurveforadruggiveninasingleoralclose.

ThemaximumplasmaconcentrationafteroraldosingisCmax,andthetimeneededtoreachmaximum
concentrationistmax.Thetmax isindependentofdoseandisdependentontherateconstantsfor
absorption(ka)andelimination(k)(Eq.7.13a).AtCmax,sometimescalledpeakconcentration,therate
ofdrugabsorbedisequaltotherateofdrugeliminated.Therefore,thenetrateofconcentrationchangeis
equaltozero.AtCmax,therateofconcentrationchangecanbeobtainedbydifferentiatingEquation7.12,
asfollows:

Page6 of28

Thiscanbesimplifiedasfollows:

AsshowninEquation7.13a,thetimeformaximumdrugconcentration,tmax,isdependentonlyonthe
rateconstantska andk.InordertocalculateCmax,thevaluefortmax isdeterminedviaEquation7.13a
andthensubstitutedintoEquation7.11,solvingforCmax.Equation7.11showsthatCmax isdirectly
proportionaltothedoseofdruggiven(D0)andthefractionofdrugabsorbed(F).Calculationoftmax and
Cmax isusuallynecessary,sincedirectmeasurementofthemaximumdrugconcentrationmaynotbe
possibleduetoimpropertimingoftheserumsamples.
Thefirstordereliminationrateconstantmaybedeterminedfromtheeliminationphaseoftheplasma
leveltimecurve(Fig.72).Atlatertimeintervals,whendrugabsorptionhasbeencompleted,ie,ekat
0,Equation7.11reducesto

Takingthenaturallogarithmofthisexpression,

Substitutionofcommonlogarithmsgives

Withthisequation,agraphconstructedbyplottinglogCpversustimewillyieldastraightlinewithaslope
ofk/2.3(Fig.76A).

Figure76.

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A.Plasmadrugconcentrationversustime,singleoraldose.B.Rateofurinarydrugexcretionversustime,single
oraldose.

Withasimilarapproach,urinarydrugexcretiondatamayalsobeusedforcalculationofthefirstorder
eliminationrateconstant.Therateofdrugexcretionafterasingleoraldoseofdrugisgivenby

wheredDu/dt=rateofurinarydrugexcretion,ke=firstorderrenalexcretionconstant,andF=fraction
ofdoseabsorbed.
AgraphconstructedbyplottingdDu/dtversustimewillyieldacurveidenticalinappearancetotheplasma
leveltimecurveforthedrug(Fig.77B).Afterdrugabsorptionisvirtuallycomplete,ekat approaches
zero,andEquation7.17reducesto

Page8 of28

Figure77.

A.Plasmadrugconcentrationversustime,singleoraldose.B.Rateofurinarydrugexcretionversustime,single
oraldose.

Takingthenaturallogarithmofbothsidesofthisexpressionandsubstitutingforcommonlogarithms,
Equation7.18becomes

Page9 of28

Whenlog(dDu/dt)isplottedagainsttime,agraphofastraightlineisobtainedwithaslopeofk/2.3
(Fig.76B).Becausetherateofurinarydrugexcretion,dDu/dt,cannotbedetermineddirectlyforany
giventimepoint,anaveragerateofurinarydrugexcretionisobtained(seealsoChapter3),andthisvalue
isplottedagainstthemidpointofthecollectionperiodforeachurinesample.
Toobtainthecumulativedrugexcretionintheurine,Equation7.17mustbeintegrated,asshownbelow.

AplotofDuversustimewillgivetheurinarydrugexcretioncurvedescribedinFigure78.Whenallofthe
drughasbeenexcreted,att=.Equation7.20reducesto

whereD u isthemaximumamountofactiveorparentdrugexcreted.

Figure78.

Cumulativeurinarydrugexcretionversustime,singleoraldose.Urinesamplesarecollectedatvarioustime
periodsafterthedose.Theamountofdrugexcretedineachsampleisaddedtotheamountofdrugrecoveredin
thepreviousurinesample(cumulativeaddition).Thetotalamountofdrugrecoveredafterallthedrugisexcreted
isD u.

DeterminationofAbsorptionRateConstantsfromOralAbsorption
Data
METHODOFRESIDUALS
Assumingka >>kinEquation7.11,thevalueforthesecondexponentialwillbecomeinsignificantlysmall
withtime(ie,ekat0)andcanthereforebeomitted.Whenthisisthecase,drugabsorptionisvirtually
complete.Equation7.11thenreducestoEquation7.22.

Fromthis,onemayalsoobtaintheinterceptoftheyaxis(Fig.79).

Page10 of28

whereAisaconstant.Thus,Equation7.22becomes

Thisequation,whichrepresentsfirstorderdrugelimination,willyieldalinearplotonsemilogpaper.The
slopeisequaltok/2.3.Thevalueforka canbeobtainedbyusingthemethodofresidualsorafeathering
technique,asdescribedinChapter4.Thevalueofkaisobtainedbythefollowingprocedure:
1.Plotthedrugconcentrationversustimeonsemilogpaperwiththeconcentrationvaluesonthe
logarithmicaxis(Fig.79).
2.Obtaintheslopeoftheterminalphase(lineBC,Fig.79)byextrapolation.
3.TakeanypointsontheupperpartoflineBC(eg,x'1,x'2,x'3,...)anddropverticallytoobtain
correspondingpointsonthecurve(eg,x1,x2,x3,...).
4.Readtheconcentrationvaluesatx1 andx'1,x2 andx'2,x3 andx'3,andsoon.Plotthevaluesof
thedifferencesatthecorrespondingtimepoints 1, 2, 3,....Astraightlinewillbeobtainedwitha
slopeofka/2.3(Fig.79).

Figure79.

Plasmaleveltimecurveforadrugdemonstratingfirstorderabsorptionandeliminationkinetics.Theequationof
thecurveisobtainedbythemethodofresiduals.

Whenusingthemethodofresiduals,aminimumofthreepointsshouldbeusedtodefinethestraightline.

Page11 of28

Datapointsoccurringshortlyaftertmax maynotbeaccurate,becausedrugabsorptionisstillcontinuingat
thattime.Becausethisportionofthecurverepresentsthepostabsorptionphase,onlydatapointsfromthe
eliminationphaseshouldbeusedtodefinetherateofdrugabsorptionasafirstorderprocess.
Ifdrugabsorptionbeginsimmediatelyafteroraladministration,theresiduallinesobtainedbyfeathering
theplasmaleveltimecurve(asshowninFig.79)willintersectontheyaxisatpointA.Thevalueofthis
yintercept,A,representsahybridconstantcomposedofka,k,VD,andFD 0.ThevalueofAhasnodirect
physiologicmeaning(seeEq.7.23).

ThevalueforA,aswellasthevaluesforkandka,maybesubstitutedbackintoEquation7.11toobtaina
generaltheoreticalequationthatwilldescribetheplasmaleveltimecurve.

LAGTIME
Insomeindividuals,absorptionofdrugafterasingleoraldosedoesnotstartimmediately,duetosuch
physiologicfactorsasstomachemptyingtimeandintestinalmotility.Thetimedelaypriortothe
commencementoffirstorderdrugabsorptionisknownaslagtime.
Thelagtimeforadrugmaybeobservedifthetworesiduallinesobtainedbyfeatheringtheoral
absorptionplasmaleveltimecurveintersectatapointgreaterthant=0onthexaxis.Thetimeatthe
pointofintersectiononthexaxisisthelagtime(Fig.710).

Figure710.

Thelagtimecanbedeterminedgraphicallyifthetworesiduallinesobtainedbyfeatheringtheplasmaleveltime
curveintersectatapointwheret>0.

Page12 of28

Thelagtime,t0,representsthebeginningofdrugabsorptionandshouldnotbeconfusedwiththe
pharmacologictermonsettime,whichrepresentslatency,eg,thetimerequiredforthedrugtoreach
minimumeffectiveconcentration.
TwoequationscanadequatelydescribethecurveinFigure710.Inone,thelagtimet0 issubtractedfrom
eachtimepoint,asshowninEquation7.24.

whereFkaD0/VD(kak)istheyvalueatthepointofintersectionoftheresiduallinesinFigure710.
ThesecondexpressionthatdescribesthecurveinFigure710omitsthelagtime,asfollows:

whereAandBrepresentstheinterceptsontheyaxisafterextrapolationoftheresiduallinesfor
absorptionandelimination,respectively.

FLIPFLOPOFKA ANDK
Inusingthemethodofresidualstoobtainestimatesofka andk,theterminalphaseofanoralabsorption
curveisusuallyrepresentedbykwhereasthesteeperslopeisrepresentedbyka(Fig.711).Inafew
cases,theeliminationrateconstantkobtainedfromoralabsorptiondatadoesnotagreewiththat
obtainedafterintravenousbolusinjection.Forexample,thekobtainedafteranintravenousbolusinjection
ofabronchodilatorwas1.72hr1,whereasthekcalculatedafteroraladministrationwas0.7hr1 (Fig.7
11).Whenka wasobtainedbythemethodofresiduals,therathersurprisingresultwasthattheka was
1.72hr 1.

Figure711.

Flipflopofka andk.Becausek>ka,therighthandfigureandslopesrepresentthecorrectvaluesforka andk.

Apparently,thekaandkobtainedbythemethodofresidualshasbeeninterchanged.Thisphenomenonis
calledflipflopoftheabsorptionandeliminationrateconstants.Flipflop,orthereversaloftherate
constants,mayoccurwheneverka andkareestimatedfromoraldrugabsorptiondata.Useofcomputer
methodsdoesnotensureagainstflipflopofthetwoconstantsestimated.

Page13 of28

Inordertodemonstrateunambiguouslythatthesteepercurverepresentstheeliminationrateforadrug
givenextravascularly,thedrugmustbegivenbyintravenousinjectionintothesamepatient.After
intravenousinjection,thedeclineinplasmadruglevelsovertimerepresentsthetrueeliminationrate.The
relationshipbetweenka andkontheshapeoftheplasmadrugconcentrationtimecurveforaconstant
doseofdruggivenorallyisshowninFigure711.
Mostofthedrugsobservedtohaveflipflopcharacteristicsaredrugswithfastelimination(ie,k>ka).
Drugabsorptionofmostdrugsolutionsorfastdissolvingproductsareessentiallycompleteoratleasthalf
completewithinanhour(ie,absorptionhalflifeof0.5or1hr,correspondingtoakaof1.38hr1 or0.69
hr1).Becausemostofthedrugsusedorallyhavelongereliminationhalflivescomparedtoabsorption
halflives,theassumptionthatthesmallerslopeorsmallerrateconstant(ie,theterminalphaseofthe
curveinFig.711)shouldbeusedastheeliminationconstantisgenerallycorrect.
Fordrugsthathavealargeeliminationrateconstant(k>0.69hr1),thechanceforflipflopofka andk
ismuchgreater.Thedrugisoproterenol,forexample,hasanoraleliminationhalflifeofonlyafew
minutes,andflipflopofka andkhasbeennoted(Portmann,1970).Similarly,salicyluricacidwasflip
floppedwhenoraldatawereplotted.Thekforsalicyluricacidwasmuchlargerthanitska (Levyetal,
1969).Manyexperimentaldrugsshowflipflopofkandka,whereasfewmarketedoraldrugsdo.Drugs
withalargekareusuallyconsideredtobeunsuitableforanoraldrugproductduetotheirlarge
eliminationrateconstant,correspondingtoaveryshorteliminationhalflife.Anextendedreleasedrug
productmayslowtheabsorptionofadrug,suchthattheka issmallerthanthekandproducingaflipflop
situation.

DETERMINATIONOFKA BYPLOTTINGPERCENTOFDRUGUNABSORBED
VERSUSTIME(WAGNERNELSONMETHOD)
Afterasingleoraldoseofadrug,thetotaldoseshouldbecompletelyaccountedforintheamountpresent
inthebody,theamountpresentintheurine,andtheamountpresentintheGItract.Therefore,dose(D
)isexpressedasfollows:

LetAb=DB +Du =amountofdrugabsorbedandletAb =amountofdrugabsorbedatt=.Atany

giventimethefractionofdrugabsorbedisAb/Ab,andthefractionofdrugunabsorbedis1(Ab/Ab).
Theamountofdrugexcretedatanytimetcanbecalculatedas

Theamountofdruginthebody(DB),atanytime,=CpVD.Atanytimet,theamountofdrugabsorbed
(Ab)is

Att=,C p =0(ie,plasmaconcentrationisnegligible),andthetotalamountofdrugabsorbedis

Thefractionofdrugabsorbedatanytimeis

Page14 of28

Thefractionunabsorbedatanytimetis

ThedrugremainingintheGItractatanytimetis

Therefore,thefractionofdrugremainingis

BecauseDGI/D0 isactuallythefractionofdrugunabsorbedthatis,1(Ab/Ab)aplotof1
(Ab/Ab)versustimegiveska/2.3astheslope(Fig.712).

Figure712.

SemiloggraphofdatainTable7.2,depictingthefractionofdrugunabsorbedversustimeusingtheWagner
Nelsonmethod.

Thefollowingstepsshouldbeusefulindeterminationofka:
1.Plotlogconcentrationofdrugversustime.
2.Findkfromtheterminalpartoftheslopewhentheslope=k/2.3.
3.Find[AUC]t 0byplottingCp versust.

Page15 of28

4.Findk[AUC]t 0 bymultiplyingeach[AUC]t 0 byk.

5.Find[AUC] 0 byaddingupallthe[AUC]pieces,fromt=0tot=
6.Determinethe1(Ab/Ab)valuecorrespondingtoeachtimepointtbyusingTable7.1.
7.Plot1(Ab/Ab)versustimeonsemilogpaper,with1(Ab/Ab)onthelogarithmicaxis.

Table7.1BloodConcentrationsandAssociatedDataforaHypotheticalDrug
ConcentrationCP (
g/mL)

[AUC]tnt

[AUC]t k[AUC]t Cp+k

[AUC]t0
0
0

0.

0.

0.

3.13

1.57

1.57

0.157

3.287

0.328 0.672

4.93

4.03

5.60

0.560

5.490

0.548 0.452

5.86

5.40

10.99

1.099

6.959

0.695 0.305

6.25

6.06

17.05

1.705

7.955

0.794 0.205

6.28

6.26

23.31

2.331

8.610

0.856 0.140

6.11

6.20

29.51

2.951

9.061

0.905 0.095

5.81

5.96

35.47

3.547

9.357

0.934 0.066

5.45

5.63

41.10

4.110

9.560

0.955 0.045

5.06

5.26

46.35

4.635

9.695

0.968 0.032

10

4.66

4.86

51.21

5.121

12

3.90

8.56

59.77

5.977

14

3.24

7.14

66.91

6.691

16

2.67

5.92

72.83

7.283

18

2.19

4.86

77.69

7.769

24

1.20

10.17

87.85

8.785

28

0.81

4.02

91.87

9.187

32

0.54

2.70

94.57

9.457

36

0.36

1.80

96.37

9.637

48

0.10

2.76

99.13

9.913

Timetn
(hr)

n1

1.000

k=0.1hr1
Ifthefractionofdrugunabsorbed,1Ab/Ab,givesalinearregressionlineonasemiloggraph,thenthe
rateofdrugabsorption,dDGI/dt,isafirstorderprocess.Recallthat1Ab/Ab isequaltodDGI/dt(Fig.
712).
Asthedrugapproaches100%absorption,Cp becomesverysmallanddifficulttoassayaccurately.
Consequently,theterminalpartofthelinedescribedby1Ab/Ab versustimetendstobecome
scatteredornonlinear.Thisterminalpartofthecurveisexcluded,andonlytheinitiallinearsegmentof
thecurveisusedfortheestimateoftheslope.

PRACTICEPROBLEM

Page16 of28

DrugconcentrationsinthebloodatvarioustimesarelistedinTable7.1.Assumingthedrugfollowsaone
compartmentmodel,findtheka,andcompareitwiththeka valueobtainedbythemethodofresiduals.
Solution
TheAUCisapproximatedbythetrapezoidalrule.Thismethodisfairlyaccuratewhentherearesufficient
datapoints.Theareabetweeneachtimepointiscalculatedas

whereCn andCn1 areconcentrations.Forexample,atn=6,the[AUC]is

Toobtain[AUC] 0,addalltheareaportionsunderthecurvefromzerotoinfinity.Inthiscase,48hours
islongenoughtobeconsideredasinfinity,becausethebloodconcentrationatthatpointalreadyhasfallen
toaninsignificantdrugconcentration,0.1 g/mL.TherestoftheneededinformationisgiveninTable7.1.
NoticethatkisobtainedfromtheplotoflogCp versustkwasfoundtobe0.1hr1.Theplotof1
(Ab/Ab)versustonsemilogpaperisshowninFigure712.
Amorecompletemethodofobtainingtheistoestimatetheresidualareafromthelastobservedplasma
concentration,Cp attn totimeequaltoinfinity.Thisequationis
n

Thetotal[AUC] 0 isthesumoftheareasobtainedbythetrapezoidalrule,[AUC] 0,andtheresidual

area[AUC] t,asdescribedinthefollowingexpression:

ESTIMATIONOFKA FROMURINARYDATA
Theabsorptionrateconstantmayalsobeestimatedfromurinaryexcretiondata,usingaplotofpercentof
drugunabsorbedversustime.Foraonecompartmentmodel:

ThedifferentialofEquation7.38withrespecttotimegives

Page17 of28

Assumingfirstordereliminationkineticswithrenaleliminationconstantke,

Assumingaonecompartmentmodel,

SubstitutingVDCp intoEquation7.39,

AndrearrangingEquation7.40,

SubstitutingfordCp/dtintoEquation7.41andkDu/ke forDE,

Whentheaboveexpressionisintegratedfromzerototimet,

Att=allthedrugthatisultimatelyabsorbedisexpressedasAb anddD u/dt=0.Thetotalamountof

drugabsorbedis

whereD u isthetotalamountofunchangeddrugexcretedintheurine.
Thefractionofdrugabsorbedatanytimetisequaltotheamountofdrugabsorbedatthistime,Abt,
dividedbythetotalamountofdrugabsorbed,Ab.

Aplotofthefractionofdrugunabsorbed,1Ab/Ab,versustimegiveska/2.3astheslopefromwhich

Page18 of28

theabsorptionrateconstantisobtained(Fig.712refertoEq.734).
Whencollectingurinarydrugsamplesforthedeterminationofpharmacokineticparameters,oneshould
obtainavalidurinecollectionasdiscussedinChapter3.Ifthedrugisrapidlyabsorbed,itmaybedifficult
toobtainmultipleearlyurinesamplestodescribetheabsorptionphaseaccurately.Moreover,drugswith
veryslowabsorptionwillhavelowconcentrations,whichmaypresentanalyticalproblems.

EFFECTOFKA ANDKONCMAX,TMAX,ANDAUC
Changesinka andkmayaffecttmax,Cmax,andAUCasshowninTable7.2.Ifthevaluesforka andk
arereversed,thenthesametmax isobtained,buttheCmax andAUCaredifferent.Iftheeliminationrate
constantiskeptat0.1hr1 andthekachangesfrom0.2to0.6hr1 (absorptionrateincreases),then
thetmaxbecomesshorter(from6.93to3.58hr),theCmax increases(from5.00to6.99 g/mL),butthe
AUCremainsconstant(100 ghr/mL).Incontrast,whentheabsorptionrateconstantiskeptat0.3hr1
andkchangesfrom0.1to0.5hr1 (eliminationrateincreases),thenthetmaxdecreases(from5.49to
2.55hr),theCmax decreases(from5.77to2.79 g/mL),andtheAUCdecreases(from100to20 g
hr/mL).Graphicalrepresentationsfortherelationshipsofka andkonthetimeforpeakabsorptionand
thepeakdrugconcentrationsareshowninFigures713and714.

Table7.2EffectsoftheAbsorptionRateConstantandEliminationRatea
Cmax (
g/mL)

AUC( g
hr/mL)

EliminationRateConstantk tmax
(hr)
(hr1)

0.1

0.2

6.93

2.50

50

0.2

0.1

6.93

5.00

100

0.3

0.1

5.49

5.77

100

0.4

0.1

4.62

6.29

100

0.5

0.1

4.02

6.69

100

0.6

0.1

3.58

6.99

100

0.3

0.1

5.49

5.77

100

0.3

0.2

4.05

4.44

50

0.3

0.3

3.33

3.68

33.3

0.3

0.4

2.88

3.16

25

0.3

0.5

2.55

2.79

20

AbsorptionRateConstantk
1

(hr )

at
=peakplasmaconcentration,Cmax =peakdrugconcentration,AUC=areaunderthecurve.
max

Valuesarebasedonasingleoraldose(100mg)thatis100%bioavailable(F=1)andhasanapparentV
of10L.Thedrugfollowsaonecompartmentopenmodel.tmaxiscalculatedbyEq.7.13andCmax is
D
calculatedbyEq.7.11.TheAUCiscalculatedbythetrapezoidalrulefrom0to24hours.

Figure713.

Page19 of28

Effectofachangeintheabsorptionrateconstant,ka,ontheplasmadrugconcentrationversustimecurve.Dose
ofdrugis100mg,V D is10L,andkis0.1hr1.

Figure714.

Effectofachangeintheeliminationrateconstant,k,ontheplasmadrugconcentrationversustimecurve.Dose
ofdrugis100mg,V D is10L,andk a is0.1hr1.

DETERMINATIONOFKA FROMTWOCOMPARTMENTORALABSORPTION
DATA(LOORIEGELMANMETHOD)

Page20 of28

Plottingthepercentofdrugunabsorbedversustimetodeterminethekamaybecalculatedforadrug
exhibitingatwocompartmentkineticmodel.Asinthemethodusedpreviouslytoobtainanestimateofthe
ka,nolimitationisplacedontheorderoftheabsorptionprocess.However,thismethoddoesrequirethat
thedrugbegivenintravenouslyaswellasorallytoobtainallthenecessarykineticconstants.
Afteroraladministrationofadoseofadrugthatexhibitstwocompartmentmodelkinetics,theamountof
drugabsorbediscalculatedasthesumoftheamountsofdruginthecentralcompartment(Dp)andinthe
tissuecompartment(Dt)andtheamountofdrugeliminatedbyallroutes(Du)(Fig.715).

Figure715.

Twocompartmentpharmacokineticmode.Drugabsorptionandeliminationoccurfromthecentralcompartment.

Eachofthesetermsmaybeexpressedintermsofkineticsconstantsandplasmadrugconcentrations,as
follows:

SubstitutingtheaboveexpressionforDp andDuintoEquation7.46,

BydividingthisequationbyVp toexpresstheequationondrugconcentrations,weobtain

Att=thisequationbecomes

Page21 of28

Equation7.53dividedbyEquation7.54givesthefractionofdrugabsorbedatanytime.

Aplotofthefractionofdrugunabsorbed,1Ab/Ab,versustimegiveska/2.3astheslopefromwhich
thevaluefortheabsorptionrateconstantisobtained(refertoEq.734).
Cp andk[AUC]t0 arecalculatedfromaplotofCp versustime.Valuesfor(Dt/Vp)canbeapproximated
bytheLooRiegelmanmethod,asfollows:

whereCt isDt/Vp,orapparenttissueconcentrationt=timeofsamplingforsamplentn1 =timeof

samplingforthesamplingpointprecedingsamplenand(Cp)t

=concentrationofdrugatcentral
n1

compartmentforsamplen1.
CalculationofCtvaluesisshowninTable7.3,usingatypicalsetoforalabsorptiondata.Aftercalculation
ofCt values,thepercentofdrugunabsorbediscalculatedwithEquation7.54,asshowninTable7.4.A
plotofpercentofdrugunabsorbedversustimeonsemiloggraphpapergivesaka ofapproximately0.5
hr1.

Table7.3CalculationofCt Valuesa
(Cp) (t)
t
n

t
n

Cp

(Cp)t (k12/k21)x
(1ek21 t)
n1

(Cp)t

(C )

(Ct)
tn

21

/k

12
t t
n1 k
n1
t
k
t
x (1e 21 ) e 21

3.00 0.5

3.0

0.5 0.218

0.134

0.218

5.20 1.0

2.2

0.5 0.160

3.00

0.134

0.402

0.187

0.749

6.50 1.5

1.3

0.5 0.094

5.20

0.134

0.697

0.642

1.433

7.30 2.0

0.8

0.5 0.058

6.50

0.134

0.871

1.228

2.157

7.60 2.5

0.3

0.5 0.022

7.30

0.134

0.978

1.849

2.849

7.75 3.0

0.15 0.5 0.011

7.60

0.134

1.018

2.442

3.471

7.70 3.5

0.5 0.004
0.05

7.75

0.134

1.039

2.976

4.019

7.60 4.0

0.5 0.007
0.10

7.70

0.134

1.032

3.444

4.469

7.10 5.0

1.0 0.073
0.50

7.60

0.250

1.900

3.276

5.103

6.60 6.0

1.0 0.073
0.50

7.10

0.250

1.775

3.740

5.442

6.00 7.0

1.0 0.087
0.60

6.60

0.250

1.650

3.989

5.552

Page22 of28

5.10 9.0

2.0 2.261
0.90

6.00

0.432

2.592

2.987

5.318

4.40 11.0
2.0 0.203
0.70

5.10

0.432

2.203

2.861

4.861

3.30 15.0
4.0 0.638
1.10

4.40

0.720

3.168

1.361

3.891

Calculatedwiththefollowingrateconstants:k12 =0.29hr1,k21 =0.311.

AdaptedwithpermissionfromLooandRiegelman(1968).

Table7.4CalculationofPercentageUnabsorbeda
(Cp)t

[AUC]tnt

[AUC]tnt k[AUC]tnt (Ct)t

n1

%Ab/V 100%Ab/V
%
p
p

0.5

3.00

0.750

0.750

0.120

0.218

3.338

16.6

83.4

1.0

5.20

2.050

2.800

0.448

0.749

6.397

31.8

68.2

1.5

6.50

2.925

5.725

0.916

1.433

8.849

44.0

56.0

2.0

7.30

3.450

9.175

1.468

2.157

10.925 54.3

45.7

2.5

7.60

3.725

12.900

2.064

2.849

12.513 62.2

37.8

3.0

7.75

3.838

16.738

2.678

3.471

13.889 69.1

30.9

3.5

7.70

3.863

20.601

3.296

4.019

15.015 74.6

25.4

4.0

7.60

3.825

24.426

3.908

4.469

15.977 79.4

20.6

5.0

7.10

7.350

31.726

5.084

5.103

17.287 85.9

14.1

6.0

6.60

6.850

38.626

6.180

5.442

18.222 90.6

9.4

7.0

6.00

6.300

44.926

7.188

5.552

18.740 93.1

6.9

9.0

5.10

11.100

56.026

8.964

5.318

19.382 96.3

3.7

11.0

4.40

9.500

65.526

10.484

4.861

19.745 98.1

1.9

15.0

3.30

15.400

80.926

12.948

3.891

20.139 100.0

Time
(hr)

Ab/V

Forcalculationoftheka bythismethod,thedrugmustbegivenintravenouslytoallowevaluationofthe
distributionandeliminationrateconstants.FordrugsthatcannotbegivenbytheIVroute,theka cannot
becalculatedbytheLooRiegelmanmethod.Forthesedrugs,givenbytheoralrouteonly,theWagner
Nelsonmethod,whichassumesaonecompartmentmodel,maybeusedtoprovideaninitialestimateofk
.Ifthedrugisgivenintravenously,thereisnowayofknowingwhetherthereisanyvariationinthe

valuesfortheeliminationrateconstantkandthedistributiverateconstantsk12 andk21.Suchvariations
altertherateconstants.Therefore,aonecompartmentmodelisfrequentlyusedtofittheplasmacurves
afteranoralorintramusculardose.Theplasmalevelpredictedfromtheka obtainedbythismethoddoes
deviatefromtheactualplasmalevel.However,inmanyinstances,thisdeviationisnotsignificant.

Page23 of28

CUMULATIVERELATIVEFRACTIONABSORBED
Thefractionofdrugabsorbedatanytimet(Eq.7.31)maybesummedorcumulatedforeachtimeperiod
forwhichaplasmadrugsamplewasobtained.FromEquation7.31,thetermAb/Ab becomesthe
cumulativerelativefractionabsorbed(CRFA).

whereCp istheplasmaconcentrationattimet.
t

IntheWagnerNelsonequation,Ab/Ab orCRFAwilleventuallyequalunity,or100%,eventhoughthe
drugmaynotbe100%systemicallybioavailable.Thepercentofdrugabsorbedisbasedonthetotal
amountofdrugabsorbed(Ab)ratherthanthedoseD0.Becausetheamountofthedrugultimately
absorbed,Ab,isequaltok[AUC] 0,thenumeratorwillalwaysequalthedenominator,whetherthedrug
is10,20,or100%bioavailable.ThepercentofdrugabsorbedbasedonAb/Ab isthereforedifferentfrom
therealpercentofdrugabsorbedunlessF=1.However,forthecalculationofka,themethodis
acceptable.
Todeterminetherealpercentofdrugabsorbed,amodificationoftheWagnerNelsonequationwas
suggestedbyWelling(1986).Areferencedrugproductwasadministeredandplasmadrugconcentrations
weredeterminedovertime.CRFAwasthenestimatedbydividingAb/Ab ref,whereAbisthecumulative
amountofdrugabsorbedfromthedrugproductandAb ref isthecumulativefinalamountofdrug
absorbedfromareferencedosageform.Inthiscase,thedenominatorofEquation7.56ismodifiedas
follows:

wherekref and[AUC] ref aretheeliminationconstantandtheareaunderthecurvedeterminedfromthe

referenceproduct.ThetermsinthenumeratorofEquation7.57refertotheproduct,asinEquation7.56.
Eachfractionofdrugabsorbediscumulatedandplottedagainstthetimeintervalinwhichtheplasmadrug
samplewasobtained(Fig.716).AnexampleoftherelationshipofCRFAversustimefortheabsorptionof
tolazamidefromfourdifferentdrugproductsisshowninFigure717.ThedataforFigure718were
obtainedfromtheserumtolazamidelevelstimecurvesinFigure717.TheCRFAtimegraphprovidesa
visualimageoftherelativeratesofdrugabsorptionfromvariousdrugproducts.IftheCRFAtimecurveis
astraightline,thenthedrugwasabsorbedfromthedrugproductatanapparentzeroorderabsorption
rate.

Figure716.

Page24 of28

Fractionofdrugabsorbed.(WagnerNelsonmethod).

Figure717.

Meancumulativerelativefractionsoftolazamideabsorbedasafunctionoftime.
(FromWellingetal,1982,withpermission.)

Figure718.

Page25 of28

Meanserumtolazamidelevelsasafunctionoftime.
(FromWellingetal,1982,withpermission.)

SIGNIFICANCEOFABSORPTIONRATECONSTANTS
Theoverallrateofsystemicdrugabsorptionfromanorallyadministeredsoliddosageformencompasses
manyindividualrateprocesses,includingdissolutionofthedrug,GImotility,bloodflow,andtransportof
thedrugacrossthecapillarymembranesandintothesystemiccirculation.Therateofdrugabsorption
representsthenetresultofalltheseprocesses.Theselectionofamodelwitheitherfirstorderorzero
orderabsorptionisgenerallyempirical.
Theactualdrugabsorptionprocessmaybezeroorder,firstorder,oracombinationofrateprocessesthat
isnoteasilyquantitated.Formanyimmediatereleasedosageforms,theabsorptionprocessisfirstorder
duetothephysicalnatureofdrugdiffusion.Forcertaincontrolledreleasedrugproducts,therateofdrug
absorptionmaybemoreappropriatelydescribedbyazeroorderrateconstant.
Thecalculationofkaisusefulindesigningamultipledosageregimen.Knowledgeofthekaandkallows
forthepredictionofpeakandtroughplasmadrugconcentrationsfollowingmultipledosing.In
bioequivalencestudies,drugproductsaregiveninchemicallyequivalent(ie,pharmaceuticalequivalents)
doses,andtherespectiveratesofsystemicabsorptionmaynotdiffermarkedly.Therefore,forthese
studies,tmax,ortimeofpeakdrugconcentration,canbeveryusefulincomparingtherespectiveratesof
absorptionofadrugfromchemicallyequivalentdrugproducts.

FREQUENTLYASKEDQUESTIONS
1.Whatistheabsorptionhalflifeofadrugandhowisitdetermined?
2.Whenonesimulatesdrugabsorptionwiththeoralonecompartmentmodel,wouldagreater
absorptionrateconstantresultinagreateramountofdrugabsorbed?
3.Howdoyouexplainthatka isoftengreaterthankwithmostdrugs?
4.Drugclearanceisdependentondoseandareaunderthetimedrugconcentrationcurve.Woulddrug
clearancebeaffectedbytherateofabsorption?
5.InswitchingadrugfromIVtooraldosing,whatisthemostimportantconsideration?
Answers

Page26 of28

LEARNINGQUESTIONS
1.Plasmasamplesfromapatientwerecollectedafteranoralbolusdoseof10mgofanew
benzodiazepinesolutionasfollows:
Time(hr) Concentration(ng/mL)
0.25

2.85

0.50

5.43

0.75

7.75

1.00

9.84

2.00

16.20

4.00

22.15

6.00

23.01

10.00

19.09

14.00

13.90

20.00

7.97

Fromthedataabove:
a.Determinetheeliminationconstantofthedrug.
b.Determinekabyfeathering.
c.Determinetheequationthatdescribestheplasmadrugconcentrationofthenewbenzodiazepine.
2.AssumingthatthedruginQuestion1is80%absorbed,find(a)theabsorptionconstant,ka(b)the
eliminationhalflife,t1/2(c)thetmax,ortimeofpeakdrugconcentrationand(d)thevolumeof
distributionofthepatient.
3.Contrastthepercentofdrugunabsorbedmethodsforthedeterminationofrateconstantforabsorption,
ka,intermsof(a)pharmacokineticmodel,(b)routeofdrugadministration,and(c)possiblesourcesof
error.
4.Whatistheerrorinherentinthemeasurementofkaforanorallyadministereddrugthatfollowsatwo
compartmentmodelwhenaonecompartmentmodelisassumedinthecalculation?
5.Whatarethemainpharmacokineticparametersthatinfluence(a)timeforpeakdrugconcentrationand
(b)peakdrugconcentration?
6.Nameamethodofdrugadministrationthatwillprovideazeroorderinput.
7.Asingleoraldose(100mg)ofanantibioticwasgiventoanadultmalepatient(43years,72kg).From
theliterature,thepharmacokineticsofthisdrugfitaonecompartmentopenmodel.Theequationthat
bestfitsthepharmacokineticsofthedrugis

Fromtheequationabove,calculate(a)tmax,(b)Cmax,and(c)t1/2forthedruginthispatient.AssumeC
p

isin g/mLandthefirstorderrateconstantsareinhours1.

Page27 of28

8.Twodrugs,AandB,havethefollowingpharmacokineticparametersafterasingleoraldoseof500mg:
Drug k (hr1) k(hr1) VD (mL)
a

1.0

0.2

10,000

0.2

1.0

20,000

Bothdrugsfollowaonecompartmentpharmacokineticmodelandare100%bioavailable.
a.Calculatethetmax foreachdrug.
b.CalculatetheCmax foreachdrug.
9.Thebioavailabilityofphenylpropanolaminehydrochloridewasstudiedin24adultmalesubjects.The
followingdatarepresentthemeanbloodphenylpropanolaminehydrochlorideconcentrations(ng/mL)after
theoraladministrationofasingle25mgdoseofphenylpropanolaminehydrochloridesolution.
Time(hr) Concentration(ng/mL) Time(hr) Concentration(ng/mL)
0

62.98

0.25

51.33

52.32

0.5

74.05

36.08

0.75

82.91

24.88

1.0

85.11

12

11.83

1.5

81.76

18

3.88

75.51

24

1.27

a.Fromthedata,obtaintherateconstantforabsorption,ka,andtherateconstantforelimination,k,
bythemethodofresiduals.
b.Isitreasonabletoassumethatka>kforadruginasolution?Howwouldyoudetermine
unequivocallywhichrateconstantrepresentstheeliminationconstantk?
c.Fromthedata,whichmethod,WagnerNelsonorLooRiegelman,wouldbemoreappropriateto
determinetheorderoftherateconstantforabsorption?
d.Fromyourvalues,calculatethetheoreticaltmax.Howdoesyourvaluerelatetotheobservedtmax
obtainedfromthesubjects?
e.WouldyouconsiderthepharmacokineticsofphenylpropanolamineHCltofollowaonecompartment
model?Why?
Answers

REFERENCES
LevyG,AmselLP,ElliotHC:Kineticsofsalicyluricacideliminationinman.JPharmSci58:827829,1969
[PMID:5810199]
LooJCK,RiegelmanS:Newmethodforcalculatingtheintrinsicabsorptionrateofdrugs.JPharmSci
57:918928,1968[PMID:5671338]
PortmannG:Pharmacokinetics.InSwarbrickJ(ed),CurrentConceptsinthePharmaceuticalSciences,vol

Page28 of28

1.Philadelphia,Lea&Febiger,1970,Chap1
WellingPG:Pharmacokinetics:ProcessesandMathematics.ACSmonograph185.Washington,DC,
AmericanChemicalSociety,1986,pp174175
WellingPG,PatelRB,PatelUR,etal:Bioavailabilityoftolazamidefromtablets:Comparisonofinvitroand
invivoresults.JPharmSci71:1259,1982[PMID:7175719]
WagnerJG:Useofcomputersinpharmacokinetics.ClinPharmacolTher8:201218,1967[PMID:
6015601]

BIBLIOGRAPHY
BoxenbaumHG,KaplanSA:Potentialsourceoferrorinabsorptionratecalculations.JPharmacokinet
Biopharm3:257264,1975[PMID:1185523]
BoyesR,AdamsH,DuceB:Oralabsorptionanddispositionkineticsoflidocainehydrochlorideindogs.J
PharmacolExpTher174:18,1970[PMID:5424701]
DvorchikBH,VesellES:Significanceoferrorassociatedwithuseoftheonecompartmentformulato
calculateclearanceof38drugs.ClinPharmacolTher23:617623,1978[PMID:648075]
WagnerJG,NelsonE:Kineticanalysisofbloodlevelsandurinaryexcretionintheabsorptivephaseafter
singledosesofdrug.JPharmSci53:1392,1964[PMID:14253604]
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