药代动力学在新药研发中的作用.ppt

药物代谢及其动力学在新药研发中的应用药物代谢动力学的任务药效二五原则

5毫克
5天临床前实验药物代谢动力学的生物模型

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药物吸收模型absorption/distributionmodel脂层转移模型invitroabsorption/distributionmodelCaco-2TransportPathways人大肠癌细胞模型TransportPathways药物吸收机制ProbesforTransportPathways肠道吸收标准对照药物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－蛋白所调节的药物吸收－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:

ratisputonaheatingpadtomaintainbodytemperature
jejunumisexposedviaamiddlelineincision
sutures:1stismadeat5cmdistaltotheligamentofTreitz
2ndismadeatabout20cmdistalto1stone
theinletofcannula-asyringeinfusionpump
theoutletofcannula-afractioncollector
theperfusionsegmentisprecleanedbypassing10mlofblankperfusatebuffer
perfusiontimeandrate=0.1ml/minfor120min
outletperfusionsamplesarecollectedevery10min
plasmasamplesarecollectedat30,60,90and120minafterperfusion

Calculations:

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EnhancedThroughputScreening

Perfusion: 4compoundsperday(4animals)
Samplesize: timepoints 7
duplicate x2
control/drug x3
sample/perfusion 42
Totalsamples/day 168

Bioanalysis: noextraction
nostandardcurve(peakarea)
machinetime/2LCs 24hrs

Totalmanpower: animaltechx1
PKDMtechx2

Testarticleamount: 1mg/testarticle

Screeningrate: onechemotypeswith30compounds/2weekspKa=10 pKa=8.4 pKa=6.5
Preduced%=0% Preduced%=7% Preduced%=12%SAR:permeabilityvs.efficacy
实例：结构优化和吸收率和活性的分析小结：体外和离体药物吸收实验系统

体外人大肠癌细胞模型(invitroCaco-2monolayer)

离体大鼠十二指肠灌流模型(