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AppliedBiopharmaceutics&Pharmacokinetics>Chapter3.OneCompartmentOpenModel:Intravenous
BolusAdministration>

ONECOMPARTMENTOPENMODEL:INTRAVENOUSBOLUS
ADMINISTRATION:INTRODUCTION
Themostcommonandmostdesirablerouteofdrugadministrationisorallybymouthusingtablets,
capsules,ororalsolutions.Indevelopingpharmacokineticmodelstodescribeandpredictdrugdisposition
kinetically,themodelmustaccountforboththerouteofadministrationandthekineticbehaviorofthe
druginthebody.
Theonecompartmentopenmodeloffersthesimplestwaytodescribetheprocessofdrugdistributionand
eliminationinthebody.Thismodelassumesthatthedrugcanenterorleavethebody(ie,themodelis
"open"),andthebodyactslikeasingle,uniformcompartment.Thesimplestrouteofdrugadministration
fromamodelingperspectiveisarapidintravenousinjection(IVbolus).Thesimplestkineticmodelthat
describesdrugdispositioninthebodyistoconsiderthatthedrugisinjectedallatonceintoabox,or
compartment,andthatthedrugdistributesinstantaneouslyandhomogenouslythroughoutthe
compartment.Drugeliminationalsooccursfromthecompartmentimmediatelyafterinjection.
Ofcourse,thismodelisasimplisticviewofdrugdispositioninthebody,whichinrealityisinfinitelymore
complexthanasinglecompartment.Inthebody,whenadrugisgivenintheformofanIVbolus,the
entiredoseofdrugentersthebloodstreamimmediately,andthedrugabsorptionprocessisconsideredto
beinstantaneous.Inmostcases,thedrugdistributesviathecirculatorysystemtopotentiallyallthe
tissuesinthebody.Uptakeofdrugsbyvarioustissueorganswilloccuratvaryingrates,dependingonthe
bloodflowtothetissue,thelipophilicityofthedrug,themolecularweightofthedrug,andthebinding
affinityofthedrugforthetissuemass.Mostdrugsareeliminatedfromthebodyeitherthroughthekidney
and/orbybeingmetabolizedintheliver.Becauseofrapiddrugequilibrationbetweenthebloodandtissue,
drugeliminationoccursasifthedoseisalldissolvedinatankofuniformfluid(asinglecompartment)
fromwhichthedrugiseliminated.Thevolumeinwhichthedrugisdistributedistermedtheapparent
volumeofdistribution,VD.Theapparentvolumeofdistributionassumesthatthedrugisuniformly
distributedinthebody.TheVD isdeterminedfromthepreinjectedamountofthedoseinthesyringeand
theplasmadrugconcentrationresultingimmediatelyafterthedoseisinjected.
Theapparentvolumeofdistributionisaparameteroftheonecompartmentmodelandgovernsthe
plasmaconcentrationofthedrugafteragivendose.Asecondpharmacokineticparameteristhe
eliminationrateconstant,k,whichgovernstherateatwhichthedrugconcentrationinthebodydeclines
overtime.TheonecompartmentmodelthatdescribesthedistributionandeliminationafteranIVbolus
doseisgiveninFigure31.

Figure31.

Page2 of23

Pharmacokineticmodelforadrugadministeredbyrapidintravenousinjection.D B =druginbodyV D =
apparentvolumeofdistributionk=eliminationrateconstant.

Theonecompartmentopenmodeldoesnotpredictactualdruglevelsinthetissues.However,themodel
assumesthatchangesintheplasmalevelsofadrugwillresultinproportionalchangesintissuedrug
levels,sincetheirkineticprofileisconsistentwithinclusionwithinthevascularcompartmentandthe
variousdrugconcentrationswithinthecompartmentareinequilibrium.Thedruginthebody,DB,cannot
bemeasureddirectlyhowever,accessiblebodyfluids(suchasblood)canbesampledtodeterminedrug
concentrations.

ELIMINATIONRATECONSTANT
Therateofeliminationformostdrugsfromatissueorfromthebodyisafirstorderprocess,inwhichthe
rateofeliminationisdependentontheamountorconcentrationofdrugpresent.Theeliminationrate
constant,k,isafirstordereliminationrateconstantwithunitsoftime1 (eg,hr1or1/hr).Generally,
theparentoractivedrugismeasuredinthevascularcompartment.Totalremovaloreliminationofthe
parentdrugfromthiscompartmentiseffectedbymetabolism(biotransformation)andexcretion.The
eliminationrateconstantrepresentsthesumofeachoftheseprocesses:

wherekm =firstorderrateprocessofmetabolismandke =firstorderrateprocessofexcretion.There

maybeseveralroutesofeliminationofdrugbymetabolismorexcretion.Insuchacase,eachofthese
processeshasitsownfirstorderrateconstant.
ArateexpressionforFigure31is

Thisexpressionshowsthattherateofeliminationofdruginthebodyisafirstorderprocess,depending
ontheoveralleliminationrateconstant,k,andtheamountofdruginthebody,DB,remainingatany
giventime,t.IntegrationofEquation3.2givesthefollowingexpression:

whereDB =druginthebodyattimetandDB 0 =druginthebodyatt=0.WhenlogDB isplotted

againsttforthisequation,astraightlineisobtained(Fig.32).Inpractice,insteadoftransformingvalues
ofDB totheircorrespondinglogarithms,eachvalueofDB isplacedatlogarithmicintervalsonsemilog
paper.

Page3 of23

Figure32.

Semiloggraphoftherateofdrugeliminationinaonecompartmentmodel.

Equation3.3canalsobeexpressedas

APPARENTVOLUMEOFDISTRIBUTION
Ingeneral,drugequilibratesrapidlyinthebody.Whenplasmaoranyotherbiologiccompartmentis
sampledandanalyzedfordrugcontent,theresultsareusuallyreportedinunitsofconcentrationinsteadof
amount.Eachindividualtissueinthebodymaycontainadifferentconcentrationofdrugduetodifferences
indrugaffinityforthattissue.Therefore,theamountofdruginagivenlocationcanberelatedtoits
concentrationbyaproportionalityconstantthatreflectsthevolumeoffluidthedrugisdissolvedin.The
volumeofdistributionrepresentsavolumethatmustbeconsideredinestimatingtheamountofdrugin
thebodyfromtheconcentrationofdrugfoundinthesamplingcompartment.Thevolumeofdistributionis
alsotheapparentvolume(VD)inwhichthedrugisdissolved(Eq.3.5).Becausethevalueofthevolume
ofdistributiondoesnothaveatruephysiologicmeaningintermsofananatomicspace,thetermapparent
volumeofdistributionisused.
Theamountofdruginthebodyisnotdetermineddirectly.Instead,abloodsampleisremovedatperiodic
intervalsandanalyzedforitsconcentrationofdrug.TheVD relatestheconcentrationofdruginplasma(C
)andtheamountofdruginthebody(DB),asinthefollowingequation:

BysubstitutingEquation3.5intoEquation3.3,asimilarexpressionbasedondrugconcentrationinplasma
isobtainedforthefirstorderdeclineofdrugplasmalevels:

Page4 of23

whereCp =concentrationofdruginplasmaattimetandCp 0 =concentrationofdruginplasmaatt=

0.Equation3.6canalsobeexpressedas

Therelationshipbetweenapparentvolume,drugconcentration,andtotalamountofdrugmaybebetter
understoodbythefollowingexample.

Example
Exactly1gofadrugisdissolvedinanunknownvolumeofwater.Uponassay,theconcentrationofthis
solutionis1mg/mL.Whatistheoriginalvolumeofthissolution?
Theoriginalvolumeofthesolutionmaybeobtainedbythefollowingproportion,rememberingthat1g=
1000mg:

Therefore,theoriginalvolumewas1000mLor1L.
If,intheaboveexample,thevolumeofthesolutionisknowntobe1L,andtheconcentrationofthe
solutionis1mg/mL,then,tocalculatethetotalamountofdrugpresent,

Therefore,thetotalamountofdruginthesolutionis1000mg,or1g.
Fromtheprecedingexample,ifthevolumeofsolutioninwhichthedrugisdissolvedandthedrug
concentrationofthesolutionareknown,thenthetotalamountofdrugpresentinthesolutionmaybe
calculated.Thisrelationshipbetweendrugconcentration,volumeinwhichthedrugisdissolved,andtotal
amountofdrugpresentisgiveninthefollowingequation:

whereD=totalamountofdrug,V=totalvolume,andC=drugconcentration.FromEquation3.8,which
issimilartoEquation3.5,ifanytwoparametersareknown,thenthethirdtermmaybecalculated.
Thebodymaybeconsideredasaconstantvolumesystemorcompartment.Therefore,theapparent
volumeofdistributionforanygivendrugisgenerallyaconstant.Ifboththeconcentrationofdruginthe
plasmaandtheapparentvolumeofdistributionforthedrugareknown,thenthetotalamountofdrugin
thebody(atthetimeinwhichtheplasmasamplewasobtained)maybecalculatedfromEquation3.5.

CalculationofVolumeofDistribution
Inaonecompartmentmodel(IVadministration),theVD iscalculatedwiththefollowingequation:

Page5 of23

WhenCp 0 isdeterminedbyextrapolation,itrepresentstheinstantaneousdrugconcentration
(concentrationofdrugatt=0)afterdrugequilibrationinthebody(Fig.33).Thedoseofdruggivenby
IVbolus(rapidIVinjection)representstheamountofdruginthebody,DB 0,att=0.BecausebothDB 0
andCp 0areknownatt=0,thentheapparentvolumeofdistribution,VD,maybecalculatedfrom
Equation3.9.

Figure33.

SemiloggraphgivingthevalueofCp 0 byextrapolation.

FromEquation3.2(repeatedhere),therateofdrugeliminationis

BysubstitutionofEquation3.5,DB =VDCp,intoEquation3.2,thefollowingexpressionisobtained:

RearrangementofEquation3.10gives

AsbothkandVD areconstants,Equation3.10maybeintegratedasfollows:

Page6 of23

Equation3.12showsthatasmallchangeintime(dt)resultsinasmallchangeintheamountofdrugin
thebody,DB.
Theintegral 0CpdtrepresentstheAUC 0,whichisthesummationoftheareaunderthecurvefromt
=0tot=.Thus,theapparentVD mayalsobecalculatedfromknowledgeofthedose,eliminationrate
constant,andtheareaunderthecurve(AUC)fromt=0tot=.TheAUC 0 isusuallyestimatedbythe
trapezoidalrule(seeChapter2).Afterintegration,Equation3.12becomes

whichuponrearrangementyieldsthefollowingequation:

ThecalculationoftheapparentVD bymeansofEquation3.13isamodelindependentmethod,because
nopharmacokineticmodelisconsideredandtheAUCisdetermineddirectlybythetrapezoidalrule.

SignificanceoftheApparentVolumeofDistribution
Theapparentvolumeofdistributionisnotatruephysiologicvolume.Mostdrugshaveanapparentvolume
ofdistributionsmallerthan,orequalto,thebodymass.Forsomedrugs,thevolumeofdistributionmaybe
severaltimesthebodymass.Equation3.9showsthattheapparentVD isdependentonCp 0.Foragiven
dose,averysmallCp 0 mayoccurinthebodyduetoconcentrationofthedruginperipheraltissuesand
organs.Forthisdose,thesmallCp 0 willresultinalargeVD.
DrugswithalargeapparentVD aremoreconcentratedinextravasculartissuesandlessconcentrated
intravascularly.Ifadrugishighlyboundtoplasmaproteinsorremainsinthevascularregion,thenCp 0
willbehigher,resultinginasmallerapparentVD.Consequently,bindingofadrugtoperipheraltissuesor
toplasmaproteinswillsignificantlyaffectVD.
TheapparentVD isavolumetermthatcanbeexpressedasasimplevolumeorintermsofpercentof
bodyweight.InexpressingtheapparentVD intermsofpercentbodyweight,a1Lvolumeisassumedto
beequaltotheweightof1kg.Forexample,iftheVD is3500mLforasubjectweighing70kg,theVD
expressedaspercentofbodyweightis

IfVD isaverylargenumberie,>100%ofbodyweightthenitmaybeassumedthatthedrugis
concentratedincertaintissuecompartments.Thus,theapparentVD isausefulparameterinconsidering
therelativeamountsofdruginthevascularandintheextravasculartissues.
PharmacologistsoftenattempttoconceptualizetheapparentVD asatruephysiologicoranatomicfluid
compartment.ByexpressingtheVD intermsofpercentofbodyweight,valuesfortheVDmaybefound

Page7 of23

thatappeartocorrespondtotrueanatomicvolumes(Table3.1).However,itmaybeonlyfortuitousthat
thevaluefortheapparentVD ofadrughasthesamevalueasarealanatomicvolume.Ifadrugistobe
consideredtobedistributedinatruephysiologicvolume,thenaninvestigationisneededtotestthis
hypothesis.

Table3.1FluidintheBody
WaterCompartment

PercentofBodyWeight PercentofTotalBodyWater

Plasma

4.5

7.5

Totalextracellularwater 27.0

45.0

Totalintracellularwater 33.0

55.0

Totalbodywater

100.0

60.0

GiventheapparentVD foraparticulardrug,thetotalamountofdruginthebodyatanytimeafter
administrationofthedrugmaybedeterminedbythemeasurementofthedrugconcentrationinthe
plasma(Eq.3.5).BecausethemagnitudeoftheapparentVD isausefulindicatorfortheamountofdrug
outsidethesamplingcompartment(usuallytheblood),thelargertheapparentVD,thegreaterthe
amountofdrugintheextravasculartissues.
Foreachdrug,theapparentVD isaconstant.Incertainpathologiccases,theapparentVD forthedrug
maybealteredifthedistributionofthedrugischanged.Forexample,inedematousconditions,thetotal
bodywaterandtotalextracellularwaterincreasethisisreflectedinalargerapparentVD valueforadrug
thatishighlywatersoluble.Similarly,changesintotalbodyweightandleanbodymass(whichnormally
occurwithage)mayalsoaffecttheapparentVD.

CLEARANCE
Clearanceisameasureofdrugeliminationfromthebodywithoutidentifyingthemechanismorprocess.
Clearanceisalsodiscussedinsubsequentchapters.Clearance(drugclearance,systemicclearance,total
bodyclearance,ClT)considerstheentirebodyasadrugeliminatingsystemfromwhichmanyelimination
processesmayoccur.

DrugClearanceintheOneCompartmentModel
Thebodyisconsideredasasystemoforgansperfusedbyplasmaandbodyfluids.Drugeliminationfrom
thebodyisanongoingprocessduetobothmetabolism(biotransformation)anddrugexcretionthrough
thekidneyandotherroutes.Themechanismsofdrugeliminationarecomplex,butcollectivelydrug
eliminationfromthebodymaybequantitatedusingtheconceptofdrugclearance.Drugclearancerefers
tothevolumeofplasmafluidthatisclearedofdrugperunittime.Clearancemayalsobeconsideredas
thefractionofdrugremovedperunittimemultipliedbytheVD.Therateofdrugeliminationmaybe
expressedinseveralways,eachofwhichessentiallydescribesthesameprocess,butwithdifferentlevels
ofinsightandapplicationinpharmacokinetics.

DRUGELIMINATIONEXPRESSEDASAMOUNTPERTIMEUNIT
Theexpressionofdrugeliminationfromthebodyintermsofmassperunittime(eg,mg/min,ormg/hr)is
simple,absolute,andunambiguous.Forazeroordereliminationprocess,expressingtherateofdrug

Page8 of23

eliminationasmassperunittimeisconvenientbecausetherateisconstant(Fig.34A).Incontrast,the
rateofdrugeliminationforafirstordereliminationprocessisnotconstantandchangeswithrespectto
thedrugconcentrationinthebody.Forafirstorderelimination,drugclearanceexpressedasvolumeper
unittime(eg,L/hrormL/min)isconvenientbecauseitisaconstant.

Figure34.

Diagramillustratingthreedifferentwaysofdescribingdrugeliminationafteradoseof100mginjectedIVintoa
volumeof10mL(amouse,forexample).

DRUGELIMINATIONEXPRESSEDASVOLUMEPERTIMEUNIT
Theconceptofexpressingarateintermsofvolumeperunittimeiscommoninpharmacy.Forexample,a
patientmaybedosedattherateof2teaspoonsful(10mL)ofaliquidmedicine(10mg/mL)daily,or
alternatively,adose(weight)of100mgofthedrugdaily.
Clearanceisaconceptthatexpresses"therateofdrugremoval"intermsofvolumeofdrugsolution
removedperunittime(atwhateverdrugconcentrationinthebodyprevailingatthattime)(Fig.34B).In
contrasttoasolutioninabottle,thedrugconcentrationinthebodywillgraduallydeclinebyafirstorder
processsuchthatthemassofdrugremovedovertimeisnotconstant.Theplasmavolumeinthehealthy
stateisrelativelyconstantbecausewaterlostthroughthekidneyisrapidlyreplacedwithfluidabsorbed
fromthegastrointestinaltract.
Sinceaconstantvolumeofplasma(about120mL/mininhumans)isfilteredthroughtheglomeruliofthe
kidneys,therateofdrugremovalisdependentontheplasmadrugconcentrationatalltimes.This
observationisbasedonafirstorderprocessgoverningdrugelimination.Formanydrugs,therateofdrug
eliminationisdependentontheplasmadrugconcentration,multipliedbyaconstantfactor(dC/dt=kC).

Page9 of23

Whentheplasmadrugconcentrationishigh,therateofdrugremovalishigh,andviceversa.
Clearance(volumeoffluidremovedofdrug)forafirstorderprocessisconstantregardlessofthedrug
concentrationbecauseclearanceisexpressedinvolumeperunittimeratherthandrugamountperunit
time.Mathematically,therateofdrugeliminationissimilartoEquation3.10:

DividingthisexpressiononbothsidesbyCp yieldsEquation3.14:

wheredDB/dtistherateofdrugeliminationfromthebody(mg/hr),Cp istheplasmadrugconcentration
(mg/L),kisafirstorderrateconstant(hr1 or1/hr),andVD istheapparentvolumeofdistribution(L).
ClisclearanceandhastheunitsL/hrinthisexample.IntheexampleinFig.34B,ClisinmL/min.
Clearance,Cl,isexpressedasvolume/time.Equation3.15showsthatclearanceisaconstantbecauseVD
andkarebothconstants.DB istheamountofdruginthebody,anddDB/dtistherateofchange(of
amount)ofdruginthebodywithrespecttotime.Thenegativesignreferstothedrugexitingfromthe
body.

DRUGELIMINATIONEXPRESSEDASFRACTIONELIMINATEDPERTIME
UNIT
Consideracompartmentvolume,containingVD liters.IfClisexpressedinlitersperminute(L/min),then
thefractionofdrugclearedperminuteinthebodyisequaltoCl/VD.
Expressingdrugeliminationasthefractionoftotaldrugeliminatedisapplicableregardlessorwhetherone
isdealingwithanamountoravolume(Fig.34C).Thisapproachismostflexibleandconvenientbecause
ofitsdimensionlessnature.Thus,itisvalidtoexpressdrugeliminationasafraction(eg,onetenthofthe
amountofdruginthebodyiseliminatedoronetenthofthedrugvolumeiseliminated).
Pharmacokineticistshaveincorporatedthisconceptintothefirstorderequation(ie,k)thatdescribesdrug
eliminationfromtheonecompartmentmodel.Indeed,theuniversalnatureofmanyprocessesformsthe
basisofthefirstorderequationofdrugelimination(eg,afractionofthetotaldrugmoleculesinthebody
willperfusetheglomeruli,afractionofthefiltereddrugmoleculeswillbereabsorbedattherenaltubules,
andafractionofthefiltereddrugmoleculeswillbeexcretedfromthebodygivinganoverallfirstorder
drugeliminationrateconstant,k).Therateofdrugeliminationistheproductofkandthedrug
concentration(Eq.3.2a).Thefirstorderequationofdrugeliminationcanbealsobasedonprobabilityand
aconsiderationofthestatisticalmomenttheory(Chapter20).

CLEARANCEANDVOLUMEOFDISTRIBUTIONRATIO,CL/VD
Example

Page10 of23

Considerthat100mgofdrugisdissolvedin10mLoffluidand10mgofdrugisremovedinthefirst
minute.Thedrugeliminationprocesscouldbedescribedas:
a.Numberofmgofdrugeliminatedperminute(mg/min)
b.NumberofmLoffluidclearedofdrugperminute
c.Fractionofdrugeliminatedperminute
TherelationshipofthethreedrugeliminationprocessesisillustratedinFigure34AC.NotethatinFigure
34C,thefractionCl/VD isdependentonboththevolumeofdistributionandtherateofdrugclearance
fromthebody.Thisclearanceconceptformsthebasisofclassicalpharmacokineticsandislaterextended
toflowmodelsinpharmacokineticmodeling.IfthedrugconcentrationisCp,therateofdrugelimination
(intermsofrateofchangeinconcentration,dCp/dt)is:

Forafirstorderprocess,

Equatingthetwoexpressionsyields:

Thus,afirstorderrateconstantisthefractionalconstantCl/VD.Somepharmacokineticistsregarddrug
clearanceandthevolumeofdistributionasindependentparametersthatarenecessarytodescribethe
timecourseofdrugelimination.Equation3.19isarearrangementofEquation3.15givenearlier.

OneCompartmentModelEquationinTermsofClandVD
Equation3.20mayberewrittenintermsofclearanceandvolumeofdistributionbysubstitutingCl/VDfor
k.Theclearanceconceptmayalsobeappliedabiologicsysteminphysiologicmodelingwithouttheneed
ofatheoreticalcompartment.

Equation3.21isapplieddirectlyinclinicalpharmacytodetermineclearanceandvolumeofdistributionin
patients.Whenonlyonesampleisavailable,ie,Cp isknownatonesampletimepoint,tafteragiven
dose,theequationcannotbedeterminedunambiguouslybecausetwounknownparametersmustbe
solved,ie,ClandVD.Inpractice,themeanvaluesforClandVD ofadrugareobtainedfromthe
populationvalues(derivedfromalargepopulationofsubjectsorpatients)intheliterature.Thevaluesof
ClandVD forthepatientareadjustedusingacomputerprogram.Ultimately,anewpairofClandVD
valuesthatbetterfittheobservedplasmadrugconcentrationisfound.Theprocessisrepeatedthrough

Page11 of23

iterationsuntilthe"best"parametersareobtained.Sincemanymathematicaltechniques(algorithms)are
availableforiteration,differentresultsmaybeobtainedusingdifferentiterativeprograms.Anobjective
testtodeterminetheaccuracyoftheestimatedclearanceandVD valuesistomonitorhowaccurately
thoseparameterswillpredicttheplasmalevelofthedrugafteranewdoseisgiventothepatient.In
subsequentchapters,meanpredictiveerrorwillbediscussedandcalculatedinordertodeterminethe
performanceofvariousdrugmonitoringmethodsinpractice.
TheratioofCl/VD maybecalculatedregardlessofcompartmentmodeltypeusingminimalplasma
samples.Clinicalpharmacistshaveappliedmanyvariationsofthisapproachtotherapeuticdrug
monitoringanddrugdosageadjustmentsinpatients.

PRACTICALFOCUS
Themostaccuratekineticmethodtodeterminethevolumeofdistributionandthedistributionkineticofa
druginapatientistogivethedrugbyasingleIVbolusdose.AnIVbolusdoseavoidsmanyvariables
suchasdelayed,irregular,and/orincompleteabsorptioncomparedtootherroutesofadministration.
TheIVsingledoseEquation3.22maybemodifiedtocalculatetheeliminationrateconstantorhalflifeofa
druginapatientwhentwoplasmasamplesandtheirtimeofcollectionareknown:

Ifthefirstplasmasampleistakenatt1 insteadofatzeroandcorrespondstoplasmadrugconcentration,
thenC2 istheconcentrationattimet2 andtissetto(t2 t1).

Rearranging:

where
t1 =timeoffirstsamplecollection
C1 =plasmadrugconcentrationatt1
t2 =timeofsecondsamplecollection
C2 =plasmadrugconcentrationatt2
Inaclinicalpractice,severaldrugdosesmayhavebeengiventothepatientandthepriordosingtimes
maynotbeaccuratelyknown.Ifthepharmacistjudgesthatthedruginthebodyisinadecliningphase
(ie,absorptioniscompleted),thisequationmaybeusedtodeterminethehalflifeofthedruginthe

Page12 of23

patientbytakingtwoplasmasamplesfarapartandrecordingthetimesofsampling.

ClearancefromDrugEliminatingTissues
Clearancemaybeappliedtoanyorganthatisinvolvedindrugeliminationfromthebody.Aslongasfirst
ordereliminationprocessesareinvolved,clearancerepresentsthesumoftheclearancesforeachdrug
eliminatingorganasshowninEquation3.26:

whereClR isrenalclearanceordrugclearancethroughthekidney,andClNR isnonrenalclearance

throughotherorgans.Generally,clearanceisconsideredasthesumofrenal,ClR, andnonrenaldrug
clearance,ClNR.ClNR isassumedtobedueprimarilytohepaticclearance(ClH)intheabsenceofother
significantdrugclearances,suchaseliminationthroughthelungorthebile,asshowninEquation3.27:

Drugclearanceconsidersthatthedruginthebodyisuniformlydissolvedinavolumeoffluid(apparent
volumeofdistribution,VD)fromwhichdrugconcentrationscanbemeasuredeasily.Typically,plasma
fluidconcentrationismeasuredanddrugclearanceisthencalculatedasthefixedvolumeofplasmafluid
(containingthedrug)clearedofdrugperunitoftime.Theunitsforclearancearevolume/time(eg,
mL/min,L/hr).
Alternatively,ClT maybedefinedastherateofdrugeliminationdividedbytheplasmadrug
concentration.Thus,clearanceisexpressedintermsofthevolumeofplasmacontainingdrugthatis
eliminatedperunittime.Thisclearancedefinitionisequivalenttothepreviousdefinitionandprovidesa
practicalwaytocalculateclearancebasedonplasmadrugconcentrationdata.

whereDEistheamountofdrugeliminatedanddDE/dtistherateofdrugelimination.
RearrangementofEquation3.29givesEquation3.30:

ThereforeClT isaconstantforaspecificdrugandrepresentstheslopeofthelineobtainedbyplottingdD
/dtversusCp,asshowninEquation3.30.

Fordrugsthatfollowfirstorderelimination,therateofdrugeliminationisdependentontheamountof
drugremaininginthebody.

Page13 of23

SubstitutingtheeliminationrateinEquation3.30forkCpVD inEquation3.31andsolvingforClT gives

Equation3.32:

Equation3.32showsthatclearance,ClT, istheproductofVD andk,bothofwhichareconstant.This

Equation3.32issimilartoEquation3.19shownearlier.Astheplasmadrugconcentrationdecreases
duringelimination,therateofdrugelimination,dD E/dt,willdecreaseaccordingly,butclearancewill
remainconstant.Clearancewillbeconstantaslongastherateofdrugeliminationisafirstorderprocess.
Forsomedrugs,theeliminationrateprocessismorecomplexandanoncompartmentmethodmaybe
usedtocalculatecertainpharmacokineticparameterssuchasclearance.Inthiscase,clearancecanbe
determineddirectlyfromtheplasmadrugconcentrationversustimecurveby

whereD0 isthedoseand[AUC] 0 = 0Cpdt

Because[AUC] 0 iscalculatedfromtheplasmadrugconcentrationversustimecurvefrom0toinfinity
()usingthetrapezoidalrule,nocompartmentalmodelisassumed.However,toextrapolatethedatato
infinitytoobtaintheresidual[AUC] 0 or(Cpt/k),firstordereliminationisusuallyassumed.Inthiscase,
ifthedrugfollowsthekineticsofaonecompartmentmodel,theClT isnumericallysimilartotheproduct
ofVD andkobtainedbyfittingthedatatoaonecompartmentmodel.

CALCULATIONOFKFROMURINARYEXCRETIONDATA
Theeliminationrateconstantkmaybecalculatedfromurinaryexcretiondata.Inthiscalculationthe
excretionrateofthedrugisassumedtobefirstorder.Thetermke istherenalexcretionrateconstant,
andDu istheamountofdrugexcretedintheurine.

FromEquation3.34,DB canbesubstitutedforDB 0ekt:

Takingthenaturallogarithmofbothsidesandthentransformingtocommonlogarithms,thefollowing
expressionisobtained:

AstraightlineisobtainedfromthisequationbyplottinglogdD u/dtvstimeonregularpaperoronsemilog
paperdDu/dtagainsttime(Figs.35and36).Theslopeofthiscurveisequaltok/2.3andthe
yinterceptisequaltokeDB 0.Forrapidintravenousadministration,DB 0 isequaltothedoseD0.

Page14 of23

Therefore,ifDB 0 isknown,therenalexcretionrateconstant(ke)canbeobtained.Becausebothke and

kcanbedeterminedbythismethod,thenonrenalrateconstant(knr)foranyrouteofeliminationother
thanrenalexcretioncanbefoundasfollows:

Figure35.

GraphofEquation3.36:lograteofdrugexcretionversustonregularpaper.

Figure36.

SemiloggraphofrateofdrugexcretionversustimeaccordingtoEquation3.36onsemilogpaper(intercept=k
D 0 B).

Page15 of23

Substitutionofkm forknr inEquation3.37givesEquation3.1.Becausethemajorroutesofelimination

formostdrugsarerenalexcretionandmetabolism(biotransformation),knr isapproximatelyequaltokm.

Thedrugurinaryexcretionrate(dDu/dt)cannotbedeterminedexperimentallyforanygiveninstant.
Therefore,theaveragerateofurinarydrugexcretion,Du/tisplottedagainsttheaveragetime,t*,forthe
collectionoftheurinesample.Inpractice,urineiscollectedoveraspecifiedtimeinterval,andtheurine
specimenisanalyzedfordrug.Anaverageurinaryexcretionrateisthencalculatedforthatcollection
period.TheaveragevalueofdDu/dtisplottedonasemilogarithmicscaleagainstthetimethat
correspondstothemidpoint(averagetime)ofthecollectionperiod.

PracticeProblem
AsingleIVdoseofanantibioticwasgiventoa50kgwomanatadoselevelof20mg/kg.Urineandblood
sampleswereremovedperiodicallyandassayedforparentdrug.Thefollowingdatawereobtained:
Time(hr) Cp ( g/mL) Du (mg)

0.25

4.2

160

0.50

3.5

140

1.0

2.5

200

2.0

1.25

250

4.0

0.31

188

6.0

0.08

46

Solution
Setupthefollowingtable:
Time(hr) Du (mg) Du/t

mg/hr t*(hr)

0.25

160

160/0.25 640

0.125

0.50

140

140/0.25 560

0.375

1.0

200

200/0.5 400

0.750

2.0

250

250/1

250

1.50

4.0

188

188/2

94

3.0

6.0

46

46/2

23

5.0

Heret*=midpointofcollectionperiodandt=timeintervalforcollectionofurinesample.
ConstructagraphonasemilogarithmicscaleofDu/tversust*.Theslopeofthislineshouldequalk/2.3.
Itisusuallyeasiertodeterminetheeliminationt12 directlyfromthecurveandthencalculatekfrom

Page16 of23

Inthisproblem,t1/2=1.0hrandk=0.693hr1.AsimilargraphoftheCp valuesversustshouldyield
acurvewithaslopehavingthesamevalueasthatderivedfromthepreviouscurve.Notethattheslopeof
thelogexcretionrateconstantisafunctionofeliminationrateconstantkandnotoftheurinaryexcretion
rateconstantke (Fig.36).
Analternativemethodforthecalculationoftheeliminationrateconstantkfromurinaryexcretiondatais
thesigmaminusmethod,ortheamountofdrugremainingtobeexcretedmethod.Thesigmaminus
methodissometimespreferredoverthepreviousmethodbecausefluctuationsintherateofelimination
areminimized.
Theamountofunchangeddrugintheurinecanbeexpressedasafunctionoftimethroughthefollowing
equation:

whereDuisthecumulativeamountofunchangeddrugexcretedintheurine.
Theamountofunchangeddrugthatisultimatelyexcretedintheurine,D u,canbedeterminedby
makingtimetequalto.Thus,thetermekt becomesnegligibleandthefollowingexpressionis
obtained:

SubstitutionofD u forkeD0/kinEquation3.39andrearrangementyields

Equation3.41canbewritteninlogarithmicformtoobtainalinearequation:

Equation3.42describestherelationshipfortheamountofdrugremainingtobeexcreted(D u Du)
versustime.
Alinearcurveisobtainedbygraphingthelogarithmscaleoftheamountofunchangeddrugyettobe
eliminated,log(D u Du)versustime.Onsemilogpaper,theslopeofthiscurveisk/2.3andthe
yinterceptisD u (Fig.37).

Figure37.

Page17 of23

Sigmaminusmethod,ortheamountofdrugremainingtobeexcretedmethod,forthecalculationofthe
eliminationrateconstantaccordingtoEquation3.42.

PRACTICEPROBLEM
Usingthedataintheprecedingproblem,determinetheeliminationrateconstant.
Solution
Constructthefollowingtable:
Time(hr) Du (mg) CumulativeDu D D
u
u

0.25

160

160

824

0.50

140

300

684

1.0

200

500

484

2.0

250

750

234

4.0

188

938

46

6.0

46

984

Plotlog(D u Du)versustime.Useasemilogarithmicscalefor(D u Du).Evaluatekandt1/2from

theslope.

ComparisonoftheRateandtheSigmaMinusMethods
TheratemethoddoesnotrequireknowledgeofD u,andthelossofoneurinespecimendoesnot
invalidatetheentireurinarydrugexcretionstudy.Thesigmaminusmethodrequiresanaccurate
determinationofD u,whichrequiresthecollectionofurineuntilurinarydrugexcretioniscomplete.A
smallerrorintheassessmentofD u introducesanerrorintermsofcurvatureoftheplot,becauseeach
pointisbasedonlog(D u Du)versustime.Fluctuationsintherateofdrugeliminationand

Page18 of23

experimentalerrorsincludingincompletebladderemptyingforacollectionperiodcauseappreciable
departurefromlinearityusingtheratemethod,whereastheaccuracyofthesigmaminusmethodisless
affected.Theratemethodisapplicabletozeroorderdrugeliminationprocess,whilethesigmaminus
methodisnot.Lastly,therenaldrugexcretionrateconstantmaybeobtainedfromtheratemethodbut
notfromthesigmaminusmethod.

CLINICALAPPLICATION
Thesigmaminusmethodandtheexcretionratemethodwasappliedtotheurinarydrugexcretionin
subjectsfollowingthesmokingofasinglemarijuanacigarette(Huestisetal,1996).Theurinaryexcretion
curvesof11norcarboxy9tetrahydrocannabinol(THCCOOH),ametaboliteofmarijuana,inonesubject
from24to144hoursaftersmokingonemarijuanacigaretteareshowninFigures38and39.Atotalof
199.7mgofTHCCOOHwasexcretedintheurineover7days,whichrepresents0.54%ofthetotal9
tetrahydrocannabinolavailableinthecigarette.Usingeitherurinarydrugexcretionmethod,theelimination
halflifewasdeterminedtobeabout30hours.However,theurinarydrugexcretionratemethoddatawere
morescattered(variable)andthecorrelationcoefficientrwasequalto0.744(Fig.39),comparedtothe
correlationcoefficientrof0.992usingthesigmaminusmethod(Fig.38).

Figure38.

Amountremainingtobeexcretedmethod.ThehalflifeofTHCCOOHwascalculatedtobe29.9hrfromtheslope
ofthiscurvethecorrelationcoefficientrwasequalto0.992.
(AdaptedfromHuestisetal.,1996,withpermission.)

Figure39.

Page19 of23

Excretionratemethod.ThehalflifeofTHCCOOHwascalculatedtobe30.7hrfromtheslopeofthiscurvethe
correlationcoefficientrwasequalto0.744.
(AdaptedfromHuestisetal.,1996,withpermission.)

ProblemsinObtainingValidUrinaryExcretionData
Certainfactorscanmakeitdifficulttoobtainvalidurinaryexcretiondata.Someofthesefactorsareas
follows:
1.Asignificantfractionoftheunchangeddrugmustbeexcretedintheurine.
2.Theassaytechniquemustbespecificfortheunchangeddrugandmustnotincludeinterferencedue
todrugmetabolitesthathavesimilarchemicalstructures.
3.Frequentsamplingisnecessaryforagoodcurvedescription.
4.Urinesamplesshouldbecollectedperiodicallyuntilalmostallofthedrugisexcreted.Agraphofthe
cumulativedrugexcretedversustimewillyieldacurvethatapproachesanasymptoteat"infinite"time
(Fig.310).Inpractice,approximatelyseveneliminationhalflivesareneededfor99%ofthedrugto
beeliminated.
5.VariationsinurinarypHandvolumemaycausesignificantvariationinurinaryexcretionrates.
6.Subjectsshouldbecarefullyinstructedastothenecessityofgivingacompleteurinespecimen(ie,
completelyemptyingthebladder).

Figure310.

Page20 of23

Graphshowingthecumulativeurinaryexcretionofdrugasafunctionoftime.

FREQUENTLYASKEDQUESTIONS
1.Whatisthedifferencebetweenarateandarateconstant?
2.Whydoeskalwayshavetheunit1/time(eg,hr1),regardlessofwhatconcentrationunitisplotted?
3.Ifadrugisdistributedintheonecompartmentmodel,doesitmeanthatthereisnodruginthe
tissue?
4.Howisclearancerelatedtothevolumeofdistributionandk?
5.Ifweuseaphysiologicmodel,arewedealingwithactualvolumesofbloodandtissues?Whydowe
stillusevolumesofdistributionthatoftenaregreaterthantherealphysicalvolume?
Answers

LEARNINGQUESTIONS
1.A70kgvolunteerisgivenanintravenousdoseofanantibiotic,andserumdrugconcentrationswere
determinedat2hoursand5hoursafteradministration.Thedrugconcentrationswere1.2and0.3 g/mL,
respectively.Whatisthebiologichalflifeforthisdrug,assumingfirstordereliminationkinetics?
2.A50kgwomanwasgivenasingleIVdoseofanantibacterialdrugatadoselevelof6mg/kg.Blood
samplesweretakenatvarioustimeintervals.Theconcentrationofthedrug(Cp)wasdeterminedinthe
plasmafractionofeachbloodsampleandthefollowingdatawereobtained:
t(hr) Cp ( g/mL)

0.25

8.21

0.50

7.87

1.00

7.23

3.00

5.15

6.00

3.09

12.0

1.11

18.0

0.40

Page21 of23

a.WhatarethevaluesforVD,k,andt1/2forthisdrug?
b.Thisantibacterialagentisnoteffectiveataplasmaconcentrationoflessthan2 g/mL.Whatisthe
durationofactivityforthisdrug?
c.Howlongwouldittakefor99.9%ofthisdrugtobeeliminated?
d.Ifthedoseoftheantibioticweredoubledexactly,whatwouldbetheincreaseindurationofactivity?
3.Anewdrugwasgiveninasingleintravenousdoseof200mgtoan80kgadultmalepatient.After6
hours,theplasmadrugconcentrationofdrugwas1.5mg/100mLofplasma.Assumingthattheapparent
VD is10%ofbodyweight,computethetotalamountofdruginthebodyfluidsafter6hours.Whatisthe
halflifeofthisdrug?
4.Anewantibioticdrugwasgiveninasingleintravenousbolusof4mg/kgtofivehealthymaleadults
ranginginagefrom23to38years(averageweight75kg).Thepharmacokineticsoftheplasmadrug
concentrationtimecurveforthisdrugfitsaonecompartmentmodel.Theequationofthecurvethatbest
fitsthedatais

Determinethefollowing(assumeunitsof g/mLforCp andhrfort):

a.Whatisthet1/2?
b.WhatistheVD?
c.Whatistheplasmalevelofthedrugafter4hours?
d.Howmuchdrugisleftinthebodyafter4hours?
e.Predictwhatbodywatercompartmentthisdrugmightoccupyandexplainwhyyoumadethis
prediction.
f.Assumingthedrugisnolongereffectivewhenlevelsdeclinetolessthan2 g/mL,whenshouldyou
administerthenextdose?
5.Definethetermapparentvolumeofdistribution.Whatcriteriaarenecessaryforthemeasurementof
theapparentvolumeofdistributiontobeusefulinpharmacokineticcalculations?
6.Adrughasaneliminationt1/2of6hoursandfollowsfirstorderkinetics.Ifasingle200mgdoseis
giventoanadultmalepatient(68kg)byIVbolusinjection,whatpercentofthedoseislostin24hours?
7.Aratherintoxicatedyoungman(75kg,age21)wasadmittedtoarehabilitationcenter.Hisblood
alcoholcontentwasfoundtobe210mg%.Assumingtheaverageeliminationrateofalcoholis10mLof
ethanolperhour,howlongwouldittakeforhisbloodalcoholconcentrationtodeclinetolessthanthe
legalbloodalcoholconcentrationof100mg%?(Hint:Alcoholiseliminatedbyzeroorderkinetics.)The
specificgravityofalcoholis0.8.Theapparentvolumeofdistributionforalcoholis60%ofbodyweight.
8.AsingleIVbolusinjectioncontaining500mgofcefamandolenafate(Mandol,Lilly)isgiventoanadult
femalepatient(63years,55kg)forasepticemicinfection.Theapparentvolumeofdistributionis0.1L/kg
andtheeliminationhalflifeis0.75hour.Assumingthedrugiseliminatedbyfirstorderkineticsandmay
bedescribedbyaonecompartmentmodel,calculatethefollowing:

Page22 of23

a.TheCp 0
b.Theamountofdruginthebody4hoursafterthedoseisgiven
c.Thetimeforthedrugtodeclineto0.5 g/mL,theminimuminhibitoryconcentrationforstreptococci
9.Iftheamountofdruginthebodydeclinesfrom100%ofthedose(IVbolusinjection)to25%ofthe
dosein8hours,whatistheeliminationhalflifeforthisdrug?(Assumefirstorderkinetics.)
10.Adrughasaneliminationhalflifeof8hoursandfollowsfirstordereliminationkinetics.Ifasingle
600mgdoseisgiventoanadultfemalepatient(62kg)byrapidIVinjection,whatpercentofthedoseis
eliminated(lost)in24hoursassumingtheapparentVD is400mL/kg?Whatistheexpectedplasmadrug
concentration(Cp)at24hourspostdose?
11.Fordrugsthatfollowthekineticsofaonecompartmentopenmodel,mustthetissuesandplasma
havethesamedrugconcentration?Why?
12.Anadultmalepatient(age35years,weight72kg)withaurinarytractinfectionwasgivenasingle
intravenousbolusofanantibiotic(dose=300mg).Thepatientwasinstructedtoemptyhisbladderprior
tobeingmedicated.Afterdoseadministration,thepatientsavedhisurinespecimensfordruganalysis.The
urinespecimenswereanalyzedforbothdrugcontentandsterility(lackofbacteriuria).Thedrugassays
gavethefollowingresults:
t(hr) AmountofDruginUrine(mg)
0

100

26
a.Assumingfirstorderelimination,calculatetheeliminationhalflifefortheantibioticinthispatient.
b.Whatarethepracticalproblemsinobtainingvalidurinarydrugexcretiondataforthedetermination
ofthedrugeliminationhalflife?

Answers

REFERENCES
HuestisMA,MitchellJ,ConeEJ:Prolongedurinaryexcretionofmarijuanametabolite(abstract).Committee
onProblemsofDrugDependence,SanJuan,PR,June25,1996.

BIBLIOGRAPHY
GibaldiM,NagashimaR,LevyG:Relationshipbetweendrugconcentrationinplasmaorserumandamount
ofdruginthebody.JPharmSci58:193197,1969
RiegelmanS,LooJCK,RowlandM:Shortcomingsinpharmacokineticanalysisbyconceivingthebodyto
exhibitpropertiesofasinglecompartment.JPharmSci57:117123,1968[PMID:5652110]
RiegelmanS,LooJ,RowlandM:Conceptsofvolumeofdistributionandpossibleerrorsinevaluationofthis
parameter.Science57:128133,1968[PMID:5652112]

Page23 of23

WagnerJG,NorthamJI:Estimationofvolumeofdistributionandhalflifeofacompoundafterrapid
intravenousinjection.JPharmSci58:529531,1975
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