药理学课件南开大学第三章药物代谢动力学

第二章药物代谢动力学Pharmacokinetics南开大学医学院张京玲韩姗Pharmacokinetics目的掌握药代动力学的基本概念及基本参数的计算。了解药代动力学的基本房室模型及血药浓度测定的临床意义。Pharmacokinetics 内容 财务内部控制制度的内容财务内部控制制度的内容人员招聘与配置的内容项目成本控制的内容消防安全演练内容 一级动力学与零级动力学衰减原理。药物的跨膜转运机理与影响因素。药物吸收途径，第一关卡消除，肝肠循环，生物利用度，血浆蛋白结合原理与意义，药物分布不均匀性的原因与意义，表观分布容积，药物体内转化过程及代谢产物，肝脏微粒体药物代谢酶（肝药酶及P450）的特性，诱导与抑制，药物作用的消除即代谢，排泄与储存。药物消除速率常数与药物消除率的概念。药物排泄途径与机理，药物时效关系曲线，药物血浆半衰期，连续用药时药物在体内的蓄积，稳态血浓度与首剂速效剂量。药物血浆浓度监测的应用。PharmacokineticsDispositionofdrug(ADMEsystem)Time-concentrationrelationshipEliminationkineticsDispositionofdrugDrugtransportAbsorptionDistributionMetabolismorBiotransformationExcretionDrugtransportTypeFeatureInfluencefactor①Con.gradient;②carrier;energy;③saturable;④competitiveinhibit;①FiltrationPassive②SimplediffusiontransportCarrier-mediatedtransportFacilitateddiffusionActivetransportComparison!①Molecularweight(M.W.)②LiposolublepropertyorPolarity③Ionizationdegreea.pHb.pKaFeatureFeaturePassivetransportActivetransportAnothernameDescendingtransportAscendingtransportConcentration&electrochemicalgradientObeyAgainstNeedspecialcarrierNoYesFeatureFeaturePassivetransportActivetransportNeedenergyNoYesSaturableNoYesCompetitiveinhibitNoYesTypesofdistributionSimplediffusion&filtrationRenaltubules,neuron,livercellsFeaturedbyMostdrugsFewdrugsInfluencefactorEffectMolecularweightLiposolublepropertyPolarityionizationdegree(PH&Pka)EasytotransportSmallHighLowNon-dis-associatedHardtotransportLargeLowHighDis-associatedHanderson-HasselbalchequationAbsorptionConceptRouteSpeedDegreeInfluencefactor①P.O(peros,ororal)First-passelimination②I.V(intravenous)③I.M(intramuscular④S.C(subcutaneou⑤P.r(perrectum)⑥Inhalation;sublingual;Lungs＞tongue＞rectum＞im＞sc＞po＞skin;Lungs＞tongue＞rectum＞im＞sc＞po＞skin;M.W.HydrophilicorlipophilicpHBloodflowDistributionConceptInfluencefactor①PlasmaproteinbindingFeatureResultSignificance②BarrierBlood-brainbarrier(BBB)PlacentabarrierBlood-eyebarrierMetabolismConceptPhaseResultEnzymeEnzymeinduction①PhaseⅠoxidations,reductions,hydrolysis；②PhaseⅡconjugationsSpecialenzymeNon-specialenzyme(hepaticmicrosomalmixedfunctionoxidasesystem)CytochromeP-450NADPHFlavoproteinInducersInhibitorsActivity↑or↓Toxicity↑or↓ExcretionConceptRouteKidneyFiltrationExcretionBileHepatoenteralcirculationMilkSalivaSkinLungsTime-concentrationcurvetimeMetabolismandeliminationphaseCmaxLatentperiodContinuanceperiodRemnantperiodMTCMECTmaxDrugconcentration(mg/L)AbsorptionanddistributionphaseTime-concentrationrelationshipCmaxCmaxTpeakEliminationkineticsEliminationkineticsZero-orderkineticsConceptFormulaCt=C0–Kt;0.5C0=C0–Kt1/2figureFeatureSignificanceEliminationkineticsFirst-orderkineticsConceptFormulaFigureFeaturesignificanceEliminationkineticsCompartmentmodelOne-compartmentmodelTwo-compartmentmodelThree-compartmentmodelEliminationkineticsParametersBioavailability,(F)AbsoluteFRelativeFAUC(P.O.）AUC(I.V.）AbsoluteF=×100%RelativeF=×100%(AUC：Areaunderthecurve)BiologicalEquivalentTrialAUC(trial）AUC(standard）EliminationkineticsApparentvolumeofdistribution,(Vd)DefinitionFormula：ClinicalsignificanceEliminationkineticsEliminationrateconstant,(Ke)Half-life,(t1/2)ConceptFormulaClinicalsignificanceEliminationkineticsAreaundercurve,(AUC)formulaClearance,(Cl)DefinitionFormulaClinicalsignificanceClmeansthetotalrateoftheeliminationofthedrugsbytheliverandthekidney.Itdoesn’tequaltotheeliminationspeedofthedrugs(RE).Ithasnothingtodowiththedoseofdrugs(A),butisinfluencedbythestateoftheliverandkidney.EliminationkineticsSteadystateorPlateau,(Css)CmaxTpeakDoseLoadingdose(D1)Maintenancedose(DM)P.O.I.V.练习t1/2为8h,按一级动力学消除的药物，95%被排出体外需多长时间?2.某药在体内按一级动力学消除，在其吸收达高峰后两次抽血，其血药浓度分别为180ug/ml、22.5ug/ml，两次抽血间隔9小时，该药的血浆半衰期是多少？