药代动力学在新药研发中的作用.pptx

药品代谢及其动力学在新药研发中应用药品代谢动力学任务药效二五标准5毫克5天临床前试验药品代谢动力学生物模型体外和离体模型(invitro/insitumodels)吸收模型absorption/permeability代谢模型metabolism体外推测和体内(invitro/invivocorrelation)动物模型(invivoanimalmodels)动物推测人(speciesextrapolation)排出太快/药效时间太短PlasmaconcentrationsofBCH-3840anditsmetabolite(BCH-6440)inmicedosed50mg/kgorally药品吸收模型absorption/distributionmodel脂层转移模型invitroabsorption/distributionmodelCaco-2TransportPathways人大肠癌细胞模型TransportPathways药品吸收机制ProbesforTransportPathways肠道吸收标准对照药品Glucose（蔗糖）vsInulin（木香素）主动吸收vs细胞间渗透PropranololvsMannitol被动吸收vs细胞间渗透由P－蛋白所调整药品吸收－使用P－糖蛋白抑制剂VerapamilChong,Dando&Morrison;Pharm.Res.1997FalsePositive假阳性＝低insituratintestinalperfusion(singlepass)离体大鼠十二指肠灌流模型（单循环）PerfusionProcedures:ratisputonaheatingpadtomaintainbodytemperaturejejunumisexposedviaamiddlelineincisionsutures:1stismadeat5cmdistaltotheligamentofTreitz2ndismadeatabout20cmdistalto1stonetheinletofcannula-asyringeinfusionpumptheoutletofcannula-afractioncollectortheperfusionsegmentisprecleanedbypassing10mlofblankperfusatebufferperfusiontimeandrate=0.1ml/minfor120minoutletperfusionsamplesarecollectedevery10minplasmasamplesarecollectedat30,60,90and120minafterperfusionCalculations:Permeability(Peff,cm/min)=(Q/2RLp)x(1-C’out/C’in)C’out/C’in=(Cout/Cin)x[phenolred]in/[phenolred]outInsituratintestinalpermeability(singlepass)PlasmaconcentrationsofBCH-3840anditsmetabolite(BCH-6440)inmicedosed50mg/kgorally排出太快/药效时间太短EnhancedThroughputScreeningPerfusion:4compoundsperday(4animals)Samplesize:timepoints7duplicatex2control/drugx3sample/perfusion42Totalsamples/day168Bioanalysis:noextractionnostandardcurve(peakarea)machinetime/2LCs24hrsTotalmanpower:animaltechx1PKDMtechx2Testarticleamount:1mg/testarticleScreeningrate:onechemotypeswith30compounds/2weekspKa=10pKa=8.4pKa=6.5Preduced%=0%Preduced%=7%Preduced%=12%SAR:permeabilityvs.efficacy实例：结构优化和吸收率和活性分析小结：体外和离体药品吸收试验系统体外人大肠癌细胞模型(invitroCaco-2monolayer)离体大鼠十二指肠灌流模型(insituratintestineperfusion)体内动物药品代谢动力学模型二五标准:5毫克/5天血浆浓度排出太快/药效时间太短死还是不死,这是个问题.Tobeornottobe,thisisaproblem.--哈默雷特