pharmacokinetics药动学及药效学

2020/5/24,1,Clinicalpharmacokinetics,2020/5/24,2,Forwhatapplicationswillclinicalpharmacokineticsbeused?Todeterminepharmacokineticparameters,suchast1/2,Vd,CL,AUC,k.Tostudybioavailabilityorbioequivalenceofadrug.ToindividualizedrugtherapyTomonitorthein-bodydynamicprocessofsometherapeuticdrugs.,2020/5/24,3,Linearpharmacokinetics,SingledosageregimenIntravenousadministrationIntravenousinfusion,2020/5/24,4,Extravascularadministration,2020/5/24,5,MultipledosageregimenIntravenousadministration,t,c,cssmax,cssmin,2020/5/24,6,Intavenousinfusion,2020/5/24,7,Intravenousinfusion,2020/5/24,8,Extrovenousadministration,2020/5/24,9,Extravenousadministration,tmax,2020/5/24,10,SomeconceptsofpharmacokineticsAccumulatingconcentrationLoadingdoseFluctuationpercentage,2020/5/24,11,Halflife(T1/2)Halflifeforadrugisaconstant,whichmeansthatitwillnotalterwiththechangesindose,frequencyofdosing,administrationroute,etc.Itwilltakelongerthan5ormoreT1/2foradrugtoattainsteadystateinthebloodlevelorbebasicallyeliminatedfromthebody.,2020/5/24,12,Clearance(Cl)Clearancemeanstheplasmavolumecontainingacertainamountofdrugisexcretedviaanorganorsomeorgansinoneminunteoronehour.,Ca,Cv,Bloodvolumeperminute,Q,Q,Q,ExtractionEfficientcy,Bloodflow,2020/5/24,13,Clplasma=Cltotal=Clrenal+Clliver+Cllung+.Themainorgansfordrugclearancearethekidneysandtheliver.Thekidneysareresponsiblefortheeliminationof,Smallmolecules,Hydrophilicsubstances,Biotransformationofseveraldrugs,2020/5/24,14,TheliverisresponsiblefordrugclearancebyMostdrugareclearedbythekidneys,somebytheliver,orbyboth.Volatiledrugscanalsobeeliminatedbythelungs.,Drugmetabolism,Bilesecretion,Lipophilicdrugs,2020/5/24,15,FactorsaffectingdrugclearanceincludePropertiesofdrugsGenotypeHealthystateFunctionoftheorgansresponsiblefordrugclearanceConcomitantuseofdrugs,2020/5/24,16,Atsteadystate,Ifadrugisintravenouslyinfused,Ifadrugisgivenextravascularlyintermittently,2020/5/24,17,Clearanceofadrugbyanorgancanalsobedefinedintermsoftheunboudfractionofdrugintheblood(fb),theintrinsicabilityoftheorgantoclearunbounddrugformtheblood(Clint)andbloodflowtotheorgan(Q),2020/5/24,18,IfQClint,thenTheclearanceofadrugviaanorganislimitedbytheintrinsicclearanceabilityofthisorgantothedrug(capacity-limitedelimination).QClint,thenTheclearanceofadrugviaanorganisdependentonthebloodflowtothisorgan(Flow-dependentelimination).,2020/5/24,19,Volumeofdistribution(Vd)Vdrelatestheamountofdruginthebodytotheconcentrationofdruginbloodroplasma.Itisassumedthatdrugmoleculesthatentercirculationsystemwilldistributehomogeneouslytothebodyrapidly.Actually,theyarenothomogeneouslydistributedinthebody.,2020/5/24,20,Therefore,Vdisaapparentmeasureofdrugdistributionspace,notarealone.Vd10L,mainlyinbloodVd40L,mainlyinextracellularfluidVd100L,mainlyinintracellularfluidVd100L,mainlyindeeptissues,2020/5/24,21,FactorsthatinfluenceVd,MolecularweightLipophilicityBindingaffinityforplasmaandtissueproteinsActivetransport,Drug,Patient,FatorleanExtentofperfusionofdifferenttypesoftissueHeartfailureorrenalfailure,2020/5/24,22,Two-phaseddistributionV：distributionofdrugfromwellperfusedtissuesintopoorlyperfusedtissues+eliminationofdrugV：eliminationphase,lgC,t,2020/5/24,23,Non-linearpharmacokineticsNotalldrugsfollowlinearpharmacokineticprinciplewhenusedattherapeuticdoses.Non-linearprocessofadrugcanbequantitativelydescribedwiththeequation,2020/5/24,24,AUC,2020/5/24,25,ifKmc,thenifKmc,then,Theprocessfollowsthefirstorderelimiationrate.,Theprocessfollowsthezeroorderelimiationrate.,2020/5/24,26,Ifc0bemuchgreaterthankm,AUCshouldbeproportionaltothesquareofc0.Thatistosay,alittleincreaseindosewillleadtoagreaterincreaseinAUC.Thetimeforwhichadrugstaysinthebodyisalsoprolongedwiththeincreaseofc0.,2020/5/24,27,Inalinearkineticprocess,wecanseeBloodconcentrationofadrugispositiveproportionaltoitsdosesAUCvarieswithitst1/2,k,VandClarenotrelatedtothedoseofadrug,Inanon-linearkineticprocess(Dose-dependantPK),Parametersarerelatedtothedose;Satuationstateofdisposalofadrugexists,2020/5/24,28,ApplicationsofStatisticMomenttoPharmacokinetics,Typicalcompartmentmodelisvitrualandnotalwaysfitstheactualin-bodyprocessofadrug.Themovementofadrugmoleculeinthebodyistakenasarandomcourse.So,theratiooftheconcentrationofadrugtoAUCcanberegardedasaprobabilitydensityfunctionofaindependentvariable-in-bodyresidencetimet.,2020/5/24,29,Definitionofstatisticmoment,k=00阶原点矩k=11阶原点矩k=22阶原点矩,If,2020/5/24,30,Zero-ordermoment=AUCFirst-ordermoment=MRT,MRTindicatesmeanresidencetime.,2020/5/24,31,Second-ordermoment=VRT,VRTmeansvarianceofMRT.,2020/5/24,32,2020/5/24,33,DoseregimenandPKConstantintravenousinfusionHowtodesigninfusionspeed?Apatientwithvenousembolismwasintravenouslyinfusedwithheparin.Thehalflifeheparinis0.83h,anddistributionvolumeis4.5L.ToattaintheCssof0.3U/ml,whatspeeddoesheparininfusedintothevein?,2020/5/24,34,10h,Whatdoseshouldbeinfused?Carbenicillinisintravenouslyinfusedtoapatient.Css=15mg/100mlshouldlastsfor10h,t1/2=1.0h,V=9L.,2020/5/24,35,Whatintervalandinfusionspeedshouldbeforaburnpatienttobeinfusedanantibioticatadoseof80mgwithin0.5hifbloodconcentrationshouldstaybetween8and1.4g/ml?Ke=0.322/h,t1/2=2.15h,V=17.6L,T=0.5h,t,2020/5/24,36,2020/5/24,37,intravenousinjection+intravenousinfusionItisknownthateffectiveconcentrationofcarbenicillinis200mg/L,ifthislevelisrequiredtogetimmediatelyandthenmaintained,whatthedoseinjectedintravenoulyandK0istobedesigned?T1/2=1h,V=9L,2020/5/24,38,MultipledoseregimenAdrugisgivenorallyatadoseof0.5gevery8h.ItisknownthatKa=1/h,Ke=0.1/h,V=30L,whatistheserumconcentrationofthedrugtwodayslater?,2020/5/24,39,Apatientreceivedorallyprocainamideatadoseof7.45mg/kg,oncevery4h.T1/2=3.5h,V=2L/kg,F=0.85,=?,2020/5/24,40,LoadingdoseandmaintainancedoseDm=DL-DLe-kForexample,a15mg/100mlofcarbenicillinshouldbelastedfor10h,andT1/2=1.0h,V=9L.Thequestionis(1)whatdoseofthedrugshouldbeaddedinto1Lofwaterorinjectiontoproducesolutionforinjection?(2)howfastwillthesolutionbeinfused?And(3)whatloadingdoseshouldbeintravenouslyinjected?,2020/5/24,41,2020/5/24,42,10mgofdiazepamwasintravenouslyinjectedtoinhibitGrandmalepilepsy,andwasinfusedbyK0=10mg/h0.5hlater.Doestheblooddrugconcentrationfallwithin0.5-2.5g/mlat3hafterinfusion?T1/2=55h,V=60L,2020/5/24,43,Repeatedone-pointmethodUsefulingettingKeandViftheeliminationphasefollowsthefirstorderkineticcourse.Inthismethod,thepointsshouldbesetattheeliminationphaseandtheintervalbetweenthetwopointsshouldbeequalto.,2020/5/24,44,t1,t2,2020/5/24,45,Onepointmethodatthesteadystate,2020/5/24,