chapter 1 introduction药代动力学与生物药剂学

BIOPHARMACEUTICSchengzn@theSchoolofPharmaceuticalScience,CSUAPIPharmaceuticalChemistryEfficacyToxicityBiopharm.&Pharmaco.ScreeningSFDADoseformAPIQualitystandardsefficacyToxicityBiopharm.&Pharmac.characters.PreclinicalstudyStabilityPreparationsqualitystandardStabilityNewDrugR&DSFDAPhaseIclinicstudyPharmacokineticsToleranceSFDAPhaseIIclinicstudyPharmacokineticsEffectivenessAdverseeffectsSFDAPhaseIIIclinicstudyEffectivenessAdverseeffectsSFDAApprovalConsiderationinAPIscreening给药后化合物可否被吸收，吸收的量是否是靶组织达到有效药物浓度？药动学参数是否符合用药目的？化合物是否对CYP有抑制作用或者诱导作用？化合物是否会产生毒性代谢产物？ConsiderationinPreclinicalStudy生物药剂学特征研究药物吸收机制研究:跨膜转运机制及透过系数；与P-gp

相互作用研究；主动转运机制研究。血浆蛋白结合率研究；组织分布及组织亲和力研究；靶向给药系统及靶向效率研究；研究药物代谢途径；研究药物主要代谢途径的酶催化机制；研究药物对酶的抑制或者诱导作用；物质平衡研究；药动学参数研究。ConsiderationinClincalStudy人体药动学研究；制剂生物等效性研究；特殊人群给药剂量调整。BiopharmaceuticsBiopharmaceutics:StudyonADMEADMEofDruginBodyDosageformTissuesAbsorptionDistributionSystemicCirculationMetabolismPharmacologiceffectsLiverKidneyExcretionDrugAbsorptionDosageformintravenous,oral,subcutaneous,transdermal,etc.ReleasePhysiologicfactorsTransmembraneFormulation,ExcipientPhysicochemicalcharacteristicsSystemicCirculationHowtochoosetheproperdosageform,andformulation,tomakethedrugreleasedfromthedosageforminapredictableandcharacterizablemanner.Finally,makethedrugabsorbedinapredictableandcharacterizablemanner.DrugDistributionMicroparticle,Liposome,ect.TissuesDruginSystemicCirculationNon-selectivityTransmembranePhysicochemicalcharacteristicsMolecularNon-molecularSelectivityTransmembraneTargettissuesHowtochoosetheproperdosageform,andformulation,tomakethedrugabsorbedinanon-molecularform,tomakethedistributioninapredictableandcharacterizablemanner.DrugMetabolismHowtochoosetheproperdosageform,andformulation,toincreasedrugabsorptionthroughlymphaticsystemandavoidthefirstpasseffecttoenhancethebioavailability.Sometimesuseenzymeinhibitororinducertoenhancethebioavailability.DosageformSystemicCirculationlymphaticsystembloodcapillaryliverfirstpasseffectExcretionDistributionInhibitorinduceDrugExcretionSystemicCirculationBindingdrugFreedrugGlomerularfiltrationActivetubularsecretionTubularreabsorptionUrineExcretionIncase,inhibitthetubularreabsorptionorenhancetubularreabsorptionisnecessarytoslowdownoracceleratedrugexcretion.Biopharmaceutics(definition)Biopharmaceuticsisthesciencethatexaminestheinterrelationshipofthephysicochemicalpropertiesofdrug,thedosageforminwhichthedrugisgiven,therouteofadministration,andthephysiologicfactorsontheADMEofdrug.PharmaceuticalFactors1.PhysicochemicalNature:Solubility,Stability,Particlesize,Solvate,Crystalform.2.FormulationFactors:Doseforms,disintegration,dissolution,excipients,druginteraction,manufactureprocedure,storageconditions.3.DrugadministrationOrally,intravenously,transdermal.PhysiologicFactorsSpecies,Humanrace;Gender;Age;Physiologicanddiseaseconditions;GeneticVariations;InNewDrugDevelopmentAbsorptionmechanismDistributionMetabolismpathwayCatalyzingmechanismEliminationmechanismEvaluateformulationPharmacokineticsClinicalpharmacokineticsDosageregimenPreclinicalandclinicalstudyOnthemarketStudyApproaches(1)StudyontherelationshipofdrugabsorptionandphysicochemicalpropertiesSolublePermeableStableinGIMetabolicstableGoodbioavailabilityStructure,crystalform,salify,micronization,solid-dispersion,inclusionLipophylicity,p-gpandCYP3Asubstrate.Doseformulation.Doseform,newdrugdeliverysystem.StudyApproaches(2)

Modified-releasedrugproductsdesign.Microparticleandtargeteddrugdelivery.Newmethodofdrugadministration.DissolutionandBAstudyofTCM.Newbiopharmaceuticalstudymodel.TheDevelopmentofBiopharmaceuticsBCSandBDDCSPredictdrugabsorptionby“Theruleoffive”:5H-bonddonors,10H-bondacceptors,MWT>500andLogP>5.Newdrugadministrationmethodofproteinandpeptidedrug：Aimtoincreasethebio-membranepermeabilityandenzymestability.MolecularBiopharmaceutics：Therelationshipofdrugandbio-membraneandbio-macromolecular.Theaffectofexcipientsandcarrierstructureonthebio-membranetransport.EndocytictargetingdeliverysystemandendocyticPK.Predictdrugabsorptionbymolecularstructure.Genetherapy.Studythebiopharmaceuticalpropertiesofenantiomer.NewTech.andMethodofBiopharmaceuticsCellculturemodelinbiopharmaceutics:UseCaco-2celllinetostudydrugabsorptionmechanism;useHepG2celllinetostudydrugmetabolism;useCalu-3celllinetostudydrugabsorptioninlung.Biophysicaltechnologyinbiopharmaceutics:ScanningTunnelingMicroscope(STM);Neutrondiffraction;IRandRamanspe