【文档说明】医学药代动力学在新药研发中的作用专题培训课件.ppt，共(84)页，1.763 MB，由小橙橙上传

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药代动力学在新药研发中的作用EfficacyHitsOptimizedLeadGoornogodecisionCompoundforDevelopment(CD)NEWDRUGINDNDAR&D临床实验临床前实验研究和发现药物研发的三大任务•药效Efficacy/Phar

macodynamics•安全Safety/Toxicology•药物代谢动力学DrugMetabolism/Pharmcokinetics药物代谢动力学的任务0.010.111010010000.511.522.533.54.（最大无毒性浓度）(最小有

效浓度）(最小药效时间）血浆浓度时间药效毒理药代最佳血浆浓度EfficacyHitsOptimizedLeadGoornogodecisionCompoundforDevelopment(CD)NEWDRUGINDNDAR&D临

床实验临床前实验研究和发现研究和发现阶段•能否被吸收？permeability•是否被代谢？metabolicstability•代谢产物？metaboliteidentification•代谢途径？pathwayidentifica

tion•对其它药物的影响？drug-druginteractionEfficacyHitsOptimizedLeadGoornogodecisionCompoundforDevelopment(CD)NEWDR

UGINDNDAR&D临床实验临床前实验研究和发现临床前阶段•生物利用度bioavailability•血浆浓度的线性和非线性doseescalation&proportionality•多次给药和体内积蓄multipledoses&accumulation•吸收和排泄

模式massbalance•体内分布distribution•从动物代谢推算人体代谢extrapolationEfficacyHitsOptimizedLeadGoornogodecisionCompoundforDevelopment(CD)NEWDRUGIND

NDAR&D临床实验临床前实验研究和发现临床阶段•长期毒性实验的动物选择metabolismprofilinginanimalsandhumansEfficacyHitsOptimizedLeadGoorn

ogodecisionCompoundforDevelopment(CD)NEWDRUGINDNDAR&D临床实验临床前实验研究和发现临床实验准则GoodClinicalPractice(GCP)非临床实验准则GoodLaborator

yPractice(GLP)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/药效时间太短口服吸收差/血浆浓度太低分布排泻代谢问题吸收问题蛋白质相互作用分布体积肾脏排泄肝脏代谢溶解度肠道吸收

膜通透性肠道消化早期研发阶段后期研发阶段SituationAnalysisinvitro体外metabolisminsitu离体permeabilityinvivo体内bioavailabilityPlasmaconcentr

ationsofBCH-3840anditsmetabolite(BCH-6440)inmicedosed50mg/kgorallyPoororalbioavailability06012018002004006008001000ParentMetaboliteTmax(min)6.146.53C

max(g/ml)0.0830.799AUC(g/ml/min)4.82321.810Bioavailability%2.52311.434R20.92920.9964BCH3840MetaboliteTime(min)Concentrati

on[ng/ml]药物吸收模型计算机脂溶度脂层转移细胞层转移十二指肠灌流absorption/distributionmodel脂层转移模型水相Aqueousphase水相Aqueousphase有机相OrganicphasepH

=6.5pH=7.4PermeabilityEvaluation–invitro14invitroabsorption/distributionmodelInVitro/InVivoCorrelationPooledDatafromFo

urBiostudies020406080100020406080100formulationfindingstudyBEstudy1BEstudy2Y=4.2+1.00X,R2=.987specificati

onstudy%Distributed%Absorped15Caco-2TransportPathways人大肠癌细胞模型TransportPathways药物吸收机制被动细胞间主动P糖蛋白ProbesforTransportPathways肠道吸收标准对照药物

•Transcellular（被动吸收）Propranolol,Testosterone•Paracellular（细胞间渗透）Mannitol,Inulin•Carriermediated（主动吸收）Glucose•P-Glycoproteinmediated（P－糖蛋白调节）

底物Vinblastine抑制物VerapamilGlucose（蔗糖）vsInulin（木香素）主动吸收vs细胞间渗透050100150200250020406080100Time(min)Flux050100150

200250300350400450Papp(nm/sec)day18/23/991999-8-301999-9-131999-9-211999-9-281999-10-51999-11-11999-11-81999-12-61999

-12-131999-12-202000-1-102000-1-172000-1-24TestDayMannitolPropranololPropranololvsMannitol被动吸收vs细胞间渗透020406080100120Papp(nm/sec)day18/23/991999-8

-301999-9-131999-9-211999-9-281999-10-51999-11-11999-11-81999-12-61999-12-131999-12-202000-1-102000-1-172000-

1-24TestDayVinblastineVinblastine/verapamil由P－蛋白所调节的药物吸收－使用P－糖蛋白抑制剂VerapamilOralAbsorption3-dayDrugsinHumansCaco-2(%)Kpcaffeine100227

ibuprofen100201desipramine95261acetaminophen95218propranolol90265hydrazine90155Ketoconazole76120terbutali

ne7356atenolol5030acetbutalol4029nadolol3522losartan3342mannitol1640inulin512Chong,Dando&Morrison;Pharm.Res.1997FalseP

ositive假阳性＝低FalseNegative假阴性＝高Caco-2TransportPathways人大肠癌细胞吸收模型insituratintestinalperfusion(singlepass)离体大鼠十二指肠灌流模型（单循环）METHODAnimal:MaleSprague-Daw

leyrats(250-350g),fastedovernight.Ratisanesthetizedbyurethane1.5g/kg,im.beforeperfusionstarts.Perfusate:Phosphatebuffer,pH=6.51

0mMglucosePhenolred(negativecontrol)Acetaminophen(positivecontrol)Finalconcentrationsoftestarticle=0.05-0.30mg/mLPerfusionProcedures:•ratisp

utonaheatingpadtomaintainbodytemperature•jejunumisexposedviaamiddlelineincision•sutures:1stismadeat5cmdistalto

theligamentofTreitz2ndismadeatabout20cmdistalto1stone•theinletofcannula-asyringeinfusionpump•theoutletofcannula-afractioncollector

•theperfusionsegmentisprecleanedbypassing10mlofblankperfusatebuffer•perfusiontimeandrate=0.1ml/minfor120min•outletperfusionsamplesareco

llectedevery10min•plasmasamplesarecollectedat30,60,90and120minafterperfusionCalculations:Permeability(Peff

,cm/min)=(Q/2RLp)x(1-C’out/C’in)C’out/C’in=(Cout/Cin)x[phenolred]in/[phenolred]outinsituratintestinalperfu

sion(singlepass)Insituratintestinalpermeability(singlepass)0.0000.0010.0020.0030.0040.005020406080100Per

meability(cm/min)HumanOralBioavailability(%)Predictionwithin90%interval=19/31(61.3%)In-housevalidation假阳性假阴性PlasmaconcentrationsofBCH-3840andits

metabolite(BCH-6440)inmicedosed50mg/kgorallyPoororalbioavailability06012018002004006008001000ParentMetaboli

teTmax(min)6.146.53Cmax(g/ml)0.0830.799AUC(g/ml/min)4.82321.810Bioavailability%2.52311.434R20.92920.9964BCH3840MetaboliteTime(min)Concentratio

n[ng/ml]排出太快/药效时间太短口服吸收差/血浆浓度太低分布排泻代谢问题吸收问题蛋白质相互作用分布体积肾脏排泄肝脏代谢溶解度肠道吸收膜通透性肠道消化早期研发阶段后期研发阶段SituationAnalysisinv

itro体外metabolisminsitu离体permeabilityinvivo体内bioavailabilityInSituRatIntestinalPermeability:Good506070809010011012013014015002550751

00PhenolRedAcetaminophenBCH-3840Time(min)DecreasedConcentration(%)阳性对照阴性对照受试药物EnhancedThroughputScreeningPerfusion:4compoundsperday

(4animals)Samplesize:timepoints7duplicatex2control/drugx3sample/perfusion42Totalsamples/day168Bioanalysis:noextractionnostand

ardcurve(peakarea)machinetime/2LCs24hrsTotalmanpower:animaltechx1PKDMtechx2Testarticleamount:1mg/testarticleScreeningrat

e:onechemotypeswith30compounds/2weeksNONNOSOOONONHFFFOONONNOSOOOOONHFFFOONONNOSOOOOONHFFFOOpKa=10pKa=8.4pKa=

6.5Preduced%=0%Preduced%=7%Preduced%=12%SAR:pKavs.permeability实例：结构优化和吸收率分析NONNOOONSNNNHFFFOONONNOSOOONSNNNHHChiralFFFOONONNOOO

NSNNFFFOONONNOSOOONSNN+FFFOOSAR:permeabilityvs.efficacy实例：结构优化和吸收率和活性的分析IC50=2uMPreduced%=0%IC50=0.012uMPreduced%=0%IC50=1.1

uMPreduced%=17%IC50=0.025uMPreduced%=15%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(insiturat

intestineperfusion)体内动物药物代谢动力学模型二五原则:5毫克/5天0.010.111010010000.511.522.533.54.血浆浓度时间化学药物化学药物+中药506070809010011

01201301401500255075100PhenolRedAcetaminophenBCH-3840Time(min)DecreasedConcentration(%)中药的药物代谢动力学的任务•本身的药物代谢动力学问题•对其它药物吸收的作用排出太快/

药效时间太短口服吸收差/血浆浓度太低分布排泻代谢问题吸收问题蛋白质相互作用分布体积肾脏排泄肝脏代谢溶解度肠道吸收膜通透性肠道消化早期研发阶段后期研发阶段SituationAnalysisinvitro体外metabolisminsitu离体perme

abilityinvivo体内bioavailability死还是不死,这是个问题.Tobeornottobe,thisisaproblem.--哈默雷特体内试验还是体外试验,这是个问题.Invitroorinvivo,thisisaproblem.--药代研究员

动物体内模型-----------人体内(临床试验)Invivoanimalsvs.invivohumans人体外模型---------------人体内(临床试验)Invitrohumansvs.invivohumans选择的指南•与人相似：疾病模型，药效，毒性，药物代

谢•实验成本HeartbeatandBodyweight（心率和体重）小鼠大鼠兔猴狗人38LiverweightandHepaticFlowvsBodyweight（体重，肝重和肝血流量）人狗猴兔大鼠小鼠人狗猴兔大鼠小鼠39Ant

ipyrineclearance(l/min)ratmouserabbitmonkeydoghumanClearance40InVitroModelsoftheLiver体外肝模型•Hepatocytes肝细胞•Liverslices肝切片•Li

vermicrosomes肝微粒体•LiverS-9Fraction肝S-9组分USFDAGuidanceforIndustry美国药物和食品管理局关于药物代谢实验的指南“Themostcompletepictureforhepaticmetabolismcanbeobtainedwithliv

ersystems,inwhichthecofactorsareself-sufficientandthenaturalorientationforlinkedenzymesispreserved.Isolatedhepatocytesandprecisi

on-cutsliceshavethesedesirablefeatures.”GuidanceforIndustry,DrugMetabolism/DrugInteractionStudiesintheDrugDevelopmentProcess:StudiesInVit

roCDER,CBER,U.S.FDA,1997译文：肝系统（分离的肝细胞和精确的肝切片）能为药物代谢实验提供最完全的信息，因为这个系统含有足够的天然水平的酶系。HOHOHOHOHOHOOGLUCHOOSOOHO

2-Hydroxy-EE22EE-3-GlucuronideEE2-3-SulfateConjugatesEE2EE2Hepatocytes（肝细胞）Microsomes（微粒体）Hepatocytes（肝细胞）MetabolismofEythi

nylEstradiol(EE2)肝微粒体和肝细胞的代谢功能差异Li,Hartman,Lu,CollinsandStrong,BrJClinPharmacol48,733-742(1999)PlasmaconcentrationsofBCH-3840anditsmet

abolite(BCH-6440)inmicedosed50mg/kgorallyPoororalbioavailability06012018002004006008001000ParentMetaboliteTmax(min)6.146.53Cm

ax(g/ml)0.0830.799AUC(g/ml/min)4.82321.810Bioavailability%2.52311.434R20.92920.9964BCH3840MetaboliteT

ime(min)Concentration[ng/ml]排出太快/药效时间太短口服吸收差/血浆浓度太低分布排泻代谢问题吸收问题蛋白质相互作用分布体积肾脏排泄肝脏代谢溶解度肠道吸收膜通透性肠道消化早期研发阶段后期研发阶段S

ituationAnalysisinvitro体外metabolisminsitu离体permeabilityinvivo体内bioavailabilityReactionvolume:1.0ml,DPBSpH7.4HepaticS-9/Microso

mes:0.5mgprotien/mLSpecies:Human/Monkey/Dog/Rat/MouseSubstrateconcentration:10MNADPH:2.4mMUDPGA:1.5mMIncubation:60minat37

oCStoppingprocedure:chilledacetonitrile,3xvolumeInVitroMetabolismAssay体外肝微粒体实验1234ABCDEFEnhancedThroughputScreening（增速筛选）A-B:（空白对照）：tes

tarticle+buffer=vehiclecontrol(VC)C-D:（阴性对照）：testarticle+microsomes=negativecontrol(NC)E-F:（实验样品）：testarti

cle+microsomes+cofactors=treatedDosingsolution=timezero(T=0)4compoundsincludingpositivereference*/plate*7ethoxycoumarin

阴性对照空白对照测试样本EnhancedThroughputScreeningIncubation:4compoundsper24-wellplate15compounds+1positivecontrolperday

Samplesize:Timezeroduplicate(16x2)VCduplicate(16x2)NCduplicate(16x2)Treatedduplicate(16x2)Totalsamples/day128Bioanalysis:noextractionnostandardcur

ve(peakarea)machinetime/2LCs24hrsTotalmanpower:PKDMtechx3Testarticleamount:0.1mg/testarticleScreeningrate:onech

emotypewith60compounds/1weekHPLCprofilesofBCH-3840anditsmetabolite(BCH-6440)BCH-3840metabolite?InvitrometabolicstabilitybyrathepaticS9EfficacyHi

tsOptimizedLeadGoornogodecisionCompoundforDevelopment(CD)NEWDRUGINDNDAR&D临床实验临床前实验研究和发现研究和发现阶段•能否被吸收？permeability•

是否被代谢？metabolicstability•代谢产物？metaboliteidentification•代谢途径？pathwayidentification•对其它药物的影响？drug-druginteractionLiquidChrom

atography/MassSpectrumofBCH-3840anditsmetabolite(BCH-6440)NNNHOOHydroxylationorOxidationMH+=310MH+=294MassIdentificationHPLCprofilesofBCH-3840anditsm

etabolite(BCH-6440)PreparationofmetabolitebybulkincubationMMPP10mgmicrosomalprotein2mgBCH-3840Fractioncollectionofm

etabolitefractionationconcentrationNuclearMagneticResonanceprofilesofBCH-3840anditsmetabolite(BCH-6440)NNN

HOONNOHNHOOC5-HBCH-3840MetaboliteStructureElucidation-3-2-1012340255075100BCH-3840IC50=1.21g/ml;TI=15.97Toxicity:TC50=19.17g

/mlBCH-6440IC50=9.99g/ml;TI=1.91Concentration[g/ml]Efficacy/Cytotoxicity%NNOHNHOOInvitrotherapeuticindexofBCH-6440EfficacyHitsOptimizedLeadGoornog

odecisionCompoundforDevelopment(CD)NEWDRUGINDNDAR&D临床实验临床前实验研究和发现研究和发现阶段•能否被吸收？permeability•是否被代谢？metabolicstability•代谢产物

？metaboliteidentification•代谢途径？pathwayidentification•对其它药物的影响？drug-druginteractionInhibitorsforCYPIsoformConc(M)Furafulline(CYP1A2)10Tranylcy

promine(CYP2A6)50Sulfaphenazole(CYP2C9)25Omeprazole(CYP2C19)20Quinidine(CYP2D6)24-methylpyrazole(CYP2E1)250K

etoconazole(CYP3A4)5•ChemicalInhibition（化学抑制）•Pureenzyme（纯酶）•CorrelationAnalysis（相关分析）MetabolismPhenotyp

ing代谢途径鉴定InhibitorsforCYPIsoformConc(M)Inhibition(%ofNC)Tranylcypromine(CYP2A6)5040.2Sulfaphenazole(

CYP2C9)2514.24-methylpyrazole(CYP2E1)25067.6Ketoconazole(CYP3A4)575.2NC1A22A62C92C192D62E13A401020304050ChemicalInhibitionofCYPIsofo

rmactivityFormationofMetabolite(peakarea)MetabolismPhenotyping代谢途径鉴定EfficacyHitsOptimizedLeadGoornogodecisionCompoundforDevel

opment(CD)NEWDRUGINDNDAR&D临床实验临床前实验研究和发现研究和发现阶段•能否被吸收？permeability•是否被代谢？metabolicstability•代谢产物？metaboliteidentification•代谢途径？pathwayi

dentification•对其它药物的影响？drug-druginteractionDrug-DrugInteractions（对其它药物代谢的影响）Inhibition（抑制）potential-IC50andKimechanism-mechani

stic（机械性）competitive（竞争性）testsystem:livermicrosomes（肝微粒体）cryopreservedhepatocytes（冷冻肝细胞）Induction（诱导）testsystem:freshisolatedhepatocytes

（肝细胞）TargetEnzymesCytochromeP450s:1A2,2A6,2C8,2C9,2C19,2D6,2E1,3A4PhaseIIconjugation:glucuronidationIC50(M):0.675Good

nessofFit:0.980795%ConfidenceIntervals:5.63–8.28-5-4-3-2-10123450255075100125RWJ-67657[logM]FormationofBilirubinMonoglucuro

nide(PercentofNC)IC50(M):20.4GoodnessofFit:0.973095%ConfidenceIntervals:16.9-26.3CYP3A4CYP3A4Drug-druginteraction:inhibition抑制作用体外药效浓度=1

uM-7-6-5-4-3-2-1012345670255075100RWJ-351958[logM]FormationofBilirubinMonoglucuronide(PercentofNC)Drug-druginteraction:Induction（肝细胞诱导模型）5daysproced

ureDay0:Isolatefreshhepatocytes,viability>70%Platinghepatocytesto24-wellplate,0.7x106viablecells/wellPlatingmediareplacedwithsandwichafter

7-hourattachmentDay1:incubationforestablishingbasallevelsofCYP450isoforms.Day2:sameasDay1Day3:dosingwithtestarticlesDay4:sameasDay

3Day5:washingoutthedosingsolutionandaddingsubstratesforCYP450isoformsasbelow:1A2-ethocyresorufinO-deeth

ylation2A6-coumarin7-hydroxylation2C9-tolbutamide4-hydroxylation2C19-S-mephenytoin4-hydroxylation2D6-dextromethorphanO-demethylation2

E1-chlorzoxazone6-hydroxylation3A4-testosterone6b-hydroxylationCYP1A2VCPC2202002000012345348260[M]PC=omeprazole(50M)Resorufinformati

on(pmol/millioncells/min)CYP3A4VCPC22020020000255075348260[M]PC=rifampin(25M)6b-hydroxytestosteroneFormation(pmol/mill

ioncells/min)Drug-druginteraction:Induction诱导作用排出太快/药效时间太短口服吸收差/血浆浓度太低分布排泻代谢问题吸收问题蛋白质相互作用分布体积肾脏排泄肝脏代

谢溶解度肠道吸收膜通透性肠道消化早期研发阶段后期研发阶段SituationAnalysisinvitro体外metabolisminsitu离体permeabilityinvivo体内bioavaila

bilityEfficacyHitsOptimizedLeadGoornogodecisionCompoundforDevelopment(CD)NEWDRUGINDNDAR&D临床实验临床前实验研究和发现临床前阶段•生物利用度bioavailability•血浆浓度的线性和非线性dos

eescalation&proportionality•多次给药和体内积蓄multipledoses&accumulation•吸收和排泄模式massbalance•体内分布distribution•从动物代谢推算人体代谢extrapolation010203

04050600500100015002000250030003500LegendIVDose(mg/kg)AUCinf(g*min/mL)119%236%310%Proportionality血浆浓度的非线性提示：代谢或排泄的非线性饱和01002003004005006000255075100

125FemaleRatsOralDose(mg/kg)AUCinf(g*hr/mL)90%72%Proportionality:AUC（大鼠试验）01002003004005006000255075100125M

aleRatsOralDose(mg/kg)AUCinf(g*hr/mL)93%63%提示：药物吸收的非线性饱和TOXICOKINETICS毒物代谢动力学试验•Animal:Sprague-Dawleyrats(male&femal

e)Cynomolgusmonkey(male&female)•Singledoseescalation（线性动力学）(50,250,500mg/kg)•Multipledoseescalation（药物体内积累）(5

0,250,500mg/kg,dailyfor14days)01002003004005006000255075100125FemaleRatsOralDose(mg/kg)AUCinf(g*hr/mL)90%72%Proportional

ity:AUC（大鼠试验）01002003004005006000255075100125MaleRatsOralDose(mg/kg)AUCinf(g*hr/mL)93%63%提示：药物吸收的非线性饱和010020030040050060001020304050

60FemaleRatsOralDose(mg/kg)010020030040050060001020304050MaleRatsOralDose(mg/kg)Cmax(g/mL)73%47%56%49%Proportionality:Cmax

（大鼠试验）提示：药物吸收的非线性饱和50250500020406080100day1day14Dose(mg/kg)AUCinf(g*hr/mL)50250500020406080100Dose(mg/kg)AUCinf(g*hr/mL)

0.920.771.041.191.021.07AccumulationRatio药物积累率（大鼠）MaleratsFemalerats010020030040050060005010015020025

0FemaleOralDose(mg/kg)AUCinf(g*hr/mL)0100200300400500600050100150200250MaleOralDose(mg/kg)AUCinf(g*hr/mL)

Proportionality:AUC（猕猴）MaleMonkeyFemaleMonkey49%34%60%38%提示：药物吸收的非线性饱和0100200300400500600020406080100120OralDos

e(mg/kg)AUCinf(g*hr/mL)0100200300400500600020406080100120MaleRatsOralDose(mg/kg)Cmax(g/mL)38%31%55%32%Pr

oportionality:Cmax（猕猴）MaleMonkeyFemaleMonkey提示：药物吸收的非线性饱和MaleMonkeyFemaleMonkey502505000255075100125Dose(mg/kg)AUCinf(g*hr/mL)50

2505000255075100125Dose(mg/kg)AUCinf(g*hr/mL)day1day140.791.111.120.730.761.14AccumulationRatio药物积累率（猕猴）PhaseITrial(Singledoseescalation)临

床一期单剂量药代动力学试验•HealthyMaleSubject(n):22•OralDoses(4):100,200,400,and800mg•Timepoints(13):0.5,1,1.5,2,3,4,6,8,10,12,16,20,and24hourEfficacyH

itsOptimizedLeadGoornogodecisionCompoundforDevelopment(CD)NEWDRUGINDNDAR&D临床实验临床前实验研究和发现临床阶段•动物和人的代谢特征(长期毒性实验的动物选择)metabolismprofilinginanimal

sandhumansEvaluationofInVitroMetabolismProfilesCryopreservedHepatocytes•mouse•rat•dog•monkey•human实验药物(MW=455.59in1/2tartratesalt)[14

C]放射性比活性(23.7µCi/mg)MethodsIncubationproceduresViability(Trypanblueexclusion)>70%Finalcelldensity:2x106viablecell/mLFinalconcentrationoftes

tarticle:20µMIncubationtime:4hoursBioanalyticalmeasurementHPLC/Fractionating/Scintillation:MetabolicprofilesLC/M

S/MS:Massidentification/structureelucidationResultsTreatedvsNegativeControl0102030405002004006008001000120012007200Min

uteDPViableHumanHepatocytes速冻人肝细胞HeatedHumanHepatocytes热灭活人肝细胞0102030405002004006008001000120012007200Minute14C-Radioactivity(dpm)DPM2M3M4Meta

bolismProfilesHumanvsDogDPViableHumanHepatocytes速冻人肝细胞ViableDogHepatocytes速冻狗肝细胞0102030405002004006008001000120012

007200MinuteDPM2M30102030405002004006008001000120012007200Minute14C-Radioactivity(dpm)DPM2M3M4MetabolismProf

ilesHumanvsMonkeyViableHumanHepatocytes速冻人肝细胞ViableMonkeyHepatocytes速冻猴肝细胞010203040500200400600800100

0120012007200MinuteDPM2M3M4M10102030405002004006008001000120012007200Minute14C-Radioactivity(dpm)DPM2M3M4MetabolismProfilesHumanvsMouseViableH

umanHepatocytes速冻人肝细胞ViableMouseHepatocytes速冻小鼠肝细胞0102030405002004006008001000120012007200MinuteDPM2M3M4010203

0405002004006008001000120012007200Minute14C-Radioactivity(dpm)DPM2M3M4MetabolismProfilesHumanvsRatViableHuma

nHepatocytes速冻人肝细胞ViableRatHepatocytes速冻大鼠肝细胞0102030405002004006008001000120012007200MinuteDPM2M3M40

102030405002004006008001000120012007200Minute14C-Radioactivity(dpm)DPM2M3M4Samples[14C]Conc.ParentD1M1M2M3M4Total*MCdpm11648172NA25151512108%oftotal9

6.21.42NA0.210.120.1298.2Mousedpm14451423NA45511333.015656%oftotal92.32.70NA2.900.720.2199.0Ratdpm9781

367NA130022219812153%oftotal80.53.02NA10.71.831.6398.1Dogdpm11895197NA24490.019.012345%oftotal94.31.66NA2.050.760.1699.1Monkeydpm826243699

.01918110528812345%oftotal66.93.530.8015.58.952.3398.1Humandpm10291128NA109616913711973%oftotal86.01.07NA9.161.411.1498.9*S

umpercentageofproductovertotalradioactivity.Abbreviations:MC,mediacontrol;D1,degradedproducts;M1–4,metabolites1–4.Table1:[14C]Radio

activityprofilesof387032inincubationwithfreshly-isolatedmousehepatocytesandcryopreservedrat,dog,monkey,andhumanhepatocytes致谢Acknowledgements军

事医学科学院输血研究所/药理毒理研究所杉山雄一博士/小澤正吾博士国家外专局引进国外智力项目2004-A-034