pharmacokinetics

Chapter2PharmacokineticsDepartmentofpharmacologyM.Y.LiuPharmacokineticsTransmembranetransportProcessesofdruginthebodyBasicconceptsofpharmacokineticsPart1TransmembranetransportofdrugsBoundFreeFreeBoundLOCUSOFACTION“RECEPTORS”TISSUERESERVOIRSSYSTEMICCIRCULATIONFreeDrugBoundDrugABSORPTIONEXCRETIONBIOTRANSFORMATIONThestructureofcellmembrane？Howtotransportit？TransmembranetransportProcedureofpermeatingthroughthevariousbarriersSuchas:variouscellmembranethewallsofthecapillarythewallsoftheintestineblood-brainbarrierplacentalbarrierAbilitythatthedrugpermeatesthroughvariousmembranesTwotypesoftransmembranetransportPassivetransport(downhillmovement)Accordingtotheconcentrationgradientofthepermeatingdrug,thedirectionofdiffusionwasfromhigherconcentrationtolowerconcentration.Smallmolecules:membraneporesLargemolecules:lipiddiffusionNotrequiringenergyHavingnosaturationHavingnocarriersNotresistingcompetitiveinhibitionAffectingfactors:thesizeofmoleculelipidsolubilitypolaritydegreeofionizationthePHoftheenvironmentsuchas:fluidofbodyfluidincellblood,urineGenerallyspeakingThedrugswhichareUnionized,lowpolarityandhigherlipidsolubilityareeasytopermeatemembrane.Thedrugswhichareionized,highpolarityandlowerlipidsolubilityaredifficulttopermeatemembrane.EffectoftheenvironmentPHondrugtransportationMostofdrugsareweakacidsorweakbases.Theionizationofdrugsmaymarkedlyreducetheirabilitytopermeatemembranes.ThedegreeofionizationofdrugsisdeterminedbythesurroundingpHandtheirpKa.Foracids：Handerson-HasselbalchEquationThepKaisthepHatwhichthedrugis50%ionized.Forbases：pH和pKa算术差的变化，就会导致解离与非解离药物浓度差的指数变化，因此pH的微小变化将显著的影响药物的解离和转运。WhenthepHisdifferentfromtheintracellularandextracellularmembraneandthepassivetransportofweakacid/basedrugsareinthebalance,thedrugconcentrationofintracellularandextracellularmembranearecomparedasbelow：eg.ForweakaciddrugwhosepKaisequalto5.4unionizedionizedtotalplasmapH=7.4GastricjuicepH=1.4[HA]1[A-]100101[HA]1[A-]0.00011.0001Whendrugconcentrationoftheintracellularandextracellularmembranearebalanced,thetotalconcentrationisn’tequal;whiletheconcentrationofunionizeddrugaresame.pKa=3.4WhenthepHoftheintracellularandextracellulararenotequal,thetotalconcentrationofthedruginthetwosidesofmembranearegivenbytheequationasbelow:Foracid:Forbase:Q：WhatkindofdrugscanbeexcretedtothelatexwhichpHistendtoacidity?TheotherformsofpassivetransportFiltration:watersolubilitysmallmolecularFacilitatedtransport：（infactitisakindofpassivetransport）TransportfromhighconcentrationtolowconcentrationNotrequiringenergyRequiringcarriersegtheabsorptionofVitaminB12fromGItractThetransportationofGlucosetotheintracellularmembraneofredbloodcells.Activetransportpermeatingmembranefromlowerconcentrationtohigherconcentration.RequiringenergyRequiringcarriersBeSaturableHavingcompetitiveinhibitionSuchas:peptide,aminoacidTheconditionswhichneedactivetransportNa+-K+-ATPaseThetransmitterswereconcentratedinthevesicle.TheexcretionandsecretionofrenaltractActivetransportcanconcentratedrugsincertainorganortissue(theiodinepump)DiffusionActiveTransportBulkFlowEndocytosisIonPairFacilitatedTransportDiffusionActiveTransportBulkFlowEndocytosisIonPairFacilitatedTransportDiffusionActiveTransportBulkFlowEndocytosisIonPairFacilitatedTransportDiffusionActiveTransportBulkFlowEndocytosisIonPairFacilitatedTransportDiffusionActiveTransportBulkFlowEndocytosisIonPairFacilitatedTransportDiffusionActiveTransportBulkFlowEndocytosisIonPairFacilitatedTransportSugars,aminoacids,vitaminsDiffusionActiveTransportBulkFlowEndocytosisIonPairFacilitatedTransportMostdrugsareabsorbedanddistributedbydiffusion.Theprocessesofdrugs（ADME）药物代谢动力学PharmacokineticsAbsorptionDistributionMetabolismExcretion“ADME”•movementofdrugsinthebody•whatthebodydoestothedrugThedispositiontodrugsbylivingsystemscanbedividedintofourrelatedduration:吸收（Absorption）分布（Distribution）代谢（Metabolism）排泄（Excretion）ADME系统Metabolism+Excretion=EliminationAbsorption+Distribution+Excretion=TransportationMetabolism=TransformationAbsorptionisthetransferofadrugfromitssiteofadministrationtothebloodstream.Characters：Mostofdrugsareabsorbedbythewayofpassivetransport.Intravenousadministrationhasnoabsorption.Theabsorptivespeedaffectsthetimeofappearingeffect.Theabsorptiveextentaffectstheintensityofaction.Factorsaffectingabsorption:drugproperties:lipidsolubility、MolecularWeight,polarity,etc.RoutesofAdministration(important):Enteral;parenteralOther:Bloodflowtotheabsorptionsite;TotalsurfaceareaavailableforabsorptionContacttimeattheabsorptionsurfaceAffinitywithspecialtissueEnteraladministrationOralSublingualRectalOraladministrationFirstPassElimination(首关消除,首关代谢，首关效应）Beforethedrugreachesthesystemiccirculation,thedrugcanbemetabolizedintheliverorintestine.AsaResult,theconcentrationofdruginthesystemiccirculationwillbereduced.FIRSTPASSELIMINATIONMetabolismintheliverPortalveinBuccalcavityStomachIntestineRectumVenacavaSublingualAdministration(硝酸甘油)RectalAdministration(水合氯醛)Buccalorrectaladministrationarewaystoby-passtheliverandavoid“f