Pharmacinetic课件VIP免费

PHARMACOKINETICS“Whatthebodydoestothedrug”Pharmacokinetics(PK)ThestudyofthedispositionofadrugThedispositionofadrugincludestheprocessesofADMEAbsorptionDistributionMetabolismExcretionToxicityEliminationADMETDRUGR&DDrugdiscoveryanddevelopment•10-15yearstodevelopanewmedicine•Likelihoodofsuccess:10%•Cost$800million–1billiondollars(US)WhydrugsfailImportanceofPKstudiesPatientsmaysuffer:ToxicdrugsmayaccumulateUsefuldrugsmayhavenobenefitbecausedosesaretoosmalltoestablishtherapyAdrugcanberapidlymetabolized.RoutesOfAdministrationRoutesOfDrugAdministrationEnteralParenteralOralInjectionRectalRespiratoryTopicalAbsorptionTheprocessbywhichdrugproceedsfromthesiteofadministrationtothesiteofmeasurement(bloodstream)withinthebody.Necessaryfortheproductionofatherapeuticeffect.Mostdrugsundergogastrointestinalabsorption.ThisisextenttowhichdrugisabsorbedfromgutlumenintoportalcirculationException:IVdrugadministrationIVvsOralI.VDrugOralDrugImmediatelyDelayedcompletelyincompleteAbsorptionreliesonPassagethroughmembranestoreachthebloodpassivediffusionoflipidsolublespecies.TheProcessTheRuleofFive-formulationTherearemorethan5H-bonddonors.Themolecularweightisover500.TheLogPisover5.Therearemorethan10H-bondacceptors.Poorabsorptionorpermeationaremorelikelywhen:Absorption&IonizationNon-ioniseddrugMorelipidsolubledrugDiffuseacrosscellmembranesmoreeasilyFirstPassMetabolismBioavailability:thefractionoftheadministereddosereachingthesystemiccirculationDoseDestroyedingutNotabsorbedDestroyedbygutwallDestroyedbylivertosystemiccirculationDeterminationofbioavailabilityAdruggivenbytheintravenousroutewillhaveanabsolutebioavailabilityof1(F=1or100%bioavavailable)Whiledrugsgivenbyotherroutesusuallyhaveanabsolutebioavailabilityoflessthanone.Theabsolutebioavailabilityistheareaundercurve(AUC)non-intravenousdividedbyAUCintravenous.ToxicityThetherapeuticindexisthedegreeofseparationbetweentoxicandtherapeuticdoses.RelationshipBetweenDose,TherapeuticEffectandToxicEffect.TheTherapeuticIndexisNarrowforMostCancerDrugs100×10×DistributionThemovementofdrugfromthebloodtoandfromthetissuesDISTRIBUTIONDeterminedby:•partitioningacrossvariousmembranes•bindingtotissuecomponents•bindingtobloodcomponents(RBC,plasmaprotein)•physiologicalvolumesDISTRIBUTIONAllofthefluidinthebody(referredtoasthetotalbodywater),inwhichadrugcanbedissolved,canberoughlydividedintothreecompartments:intravascular(bloodplasmafoundwithinbloodvessels)interstitial/tissue(fluidsurroundingcells)intracellular(fluidwithincells,i.e.cytosol)Thedistributionofadrugintothesecompartmentsisdictatedbyit'sphysicalandchemicalpropertiesTOTALBODYWATERVascular3L4%BWExtravascular9L13%BWIntracellular28L41%BWDistributionApparentvolumeofdistribution(Vd)=Amtofdruginbody/plasmadrugconcVOLUMEOFDISTRIBUTIONFORSOMEDRUGSDRUGVd(L)cocaine140clonazepam210amitriptyline1050amiodarone~5000FactorsaffectingdrugsVdBloodflow:ratevarieswidelyasfunctionoftissueMuscle=slowOrgans=fastCapillarystructure:•Mostcapillariesare“leaky”anddonotimpedediffusionofdrugs•Blood-brainbarrierformedbyhighleveloftightjunctionsbetweencells•BBBisimpermeabletomostwater-solubledrugsBloodBrainBarrier•Disruptionbyosmoticmeans•Useofendogenoustransportsystems•Blockingofactiveeffluxtransporters•Intracerebralimplantation•EtcPlasmaProt...