Print|CloseWindow
Note:Largeimagesandtablesonthispagemaynecessitateprintinginlandscapemode.
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:
Thisexpressionshowsthattherateofeliminationofdruginthebodyisafirstorderprocess,depending
ontheoveralleliminationrateconstant,k,andtheamountofdruginthebody,DB,remainingatany
giventime,t.IntegrationofEquation3.2givesthefollowingexpression:
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
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:
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
CALCULATIONOFKFROMURINARYEXCRETIONDATA
Theeliminationrateconstantkmaybecalculatedfromurinaryexcretiondata.Inthiscalculationthe
excretionrateofthedrugisassumedtobefirstorder.Thetermke istherenalexcretionrateconstant,
andDu istheamountofdrugexcretedintheurine.
Takingthenaturallogarithmofbothsidesandthentransformingtocommonlogarithms,thefollowing
expressionisobtained:
AstraightlineisobtainedfromthisequationbyplottinglogdD u/dtvstimeonregularpaperoronsemilog
paperdDu/dtagainsttime(Figs.35and36).Theslopeofthiscurveisequaltok/2.3andthe
yinterceptisequaltokeDB 0.Forrapidintravenousadministration,DB 0 isequaltothedoseD0.
Page14 of23
Figure35.
GraphofEquation3.36:lograteofdrugexcretionversustonregularpaper.
Figure36.
SemiloggraphofrateofdrugexcretionversustimeaccordingtoEquation3.36onsemilogpaper(intercept=k
D 0 B).
Page15 of23
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
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
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
CopyrightTheMcGrawHillCompanies.Allrightsreserved.
PrivacyNotice.AnyuseissubjecttotheTermsofUseandNotice.