药物代谢动力学陈季强.ppt

Email:chenjq,2010-2011学年冬学期,Section.PharmacologicalBasisofTherapeutics,药物治疗学基础(治疗学的药理学基础),IntroductionofBMS,第七周,Chapter2.Pharmacokinetics,Chapter3.Factorsinfluencingeffectofdrug,Chapter4.Anti-neoplastics,Chapter1.Pharmacodynamics,Section.PharmacologicalBasisofTherapeutics,Contents,BasicConceptofPharmacology,Chapter2.Pharmacokinetics,Chapter3.Factorsinfluencingeffectofdrug,Chapter4.Anti-neoplastics,Chapter1.Pharmacodynamics,Section.PharmacologicalBasisofTherapeutics,Contents,BasicConceptofPharmacology,Chapter2Pharmacokinetics,Section.PharmacologicalBasisofTherapeutics,Part1.Transportofdrugacrosscellmembrane(药物的跨膜转运),Part2.Pharmacokineticsprocess(药物的体内过程),Part3.Therateprocessofpharmaco-kinetics(药动学过程),Chapter2.Pharmacokinetics,Contents,Part1.Transportofdrugacrosscellmembrane,Chapter2.Pharmacokinetics,Part1.Transportofdrugacrosscellmembrane,Absorption(吸收);Distribution(分布);Biotransformation(生物转化),orMetabolism(代谢);Excretion(排泄).,and:Transport(转运);and:Elimination(消除).,1.Classificationofpharmacokineticsprocess(药动学过程的分类):,Part1.Transportofdrugacrosscellmembrane,2.Thepatternsofdrugtransportacrosscellmembrane(药物跨膜转运类型):,通过脂质通过水性通过载体扩散通道扩散转运,简单扩散,滤过,主动转运,Part1.Transportofdrugacrosscellmembrane,Filtration(滤过)alongpressuregradient.Simplediffusion(简单扩散)alongconcentrationgradient.,Characteristicsofsimplediffusion:dontconsumeenergy(不耗能);neednotcarrier(不需要载体);nosaturation(无饱和现象);nocompetitiveinhibition(无竞争性抑制);todynamicequilibriumfinally(最终保持在动态稳定水平).,(1)Passivetransport(被动转运):,Part1.Transportofdrugacrosscellmembrane,Thefactorsaffectingsimplediffusion:,differenceofdrugconcentration;lipidsolubilityofthedrug,whichbedecidedbyionizabilityofdrug.TheionizabilityofdrugfollowingbypKaofdrugandpHofsolution.iontrapping(离子障),Part1.Transportofdrugacrosscellmembrane,Handerson-HasselbachFormulaWeakaciddrug(弱酸性药物):HAH+A-H+AKa=HAHAH+=A-KalogHA/A-=logH+logKalogHA/A-=pKapHWhenpH=pKa,HA=A-pHpKa,HAA-pHpKa,HAA-,Part1.Transportofdrugacrosscellmembrane,logHA/A-=pKapHEffectofpHonionizationofSalicyclicacid(水杨酸,pKa=3)pHlogHA/A-HA/A-non-ionized(%)131=2100/199.0232=110/190.0333=01/150.0434=11/1010.0535=21/1001.0636=31/10000.1,Part1.Transportofdrugacrosscellmembrane,Weakbasedrug(弱碱性药物):BH+H+BBH+Ka=BH+BKa=BH+H+logB/BH+=logKalogH+=pHpKaWhenpH=pKa,B=BH+pHpKa,BBH+pHpKa,BBH+,Part1.Transportofdrugacrosscellmembrane,Clinicalsignificance(临床意义):,口服药物,在胃肠道吸收,弱酸性药物在酸性环境的胃中容易吸收,弱碱性药物在pH较高的肠道内容易被吸收.,Part1.Transportofdrugacrosscellmembrane,改变尿液的酸碱度可以影响药物在肾小管的重吸收过程.弱酸性药物在酸性尿液中容易重吸收,因此减少了该药物在尿液中的排出,而弱酸性药物在碱性尿液中则重吸收减少,可增加该药物的排出量.这一知识在临床上可以用于治疗某些药物中毒.如催眠药苯巴比妥(酸性药物)过量中毒时,用NaHCO3静脉滴注,使尿液碱化,可减少苯巴比妥的重吸收而加速其排泄.,(2)Activetransport(主动转运)adverseconcentrationgradienttran-sport.,Characteristicsofactivetransport:needcarrier;energyconsumption;saturability;competitiveinhibitionbycongeners;activetransportstopwhennodrugatonesideofmembrane.,Part1.Transportofdrugacrosscellmembrane,Part2.Pharmacokineticsprocess,Chapter2.Pharmacokinetics,1.Absorpation:(1)Enteralingestion(胃肠道给药):Oraladministration(peros,po)Siteofabsorptionfirst-passelimination(首过消除)sublingual(舌下含服)perrectum(直肠给药),Part2.Pharmacokineticsprocess,(2)Parenteraladministration:Intravenous(iv):noabsorption.Intramuscular(i.m.),Subcutaneous(s.c.),Otheradministration:inhalation(吸入):aerosol;nebulatransdermaladministration(透皮给药),Part2.Pharmacokineticsprocess,Factorsaffectingdistribution:Regionalbloodflow,redistributionPhysicochemicalpropertiesofdrug:MW,LS,polarity,Selectivityofdrugdistribution:e.g.iodine(碘)thyroid(甲状腺)Biologicalbarriers:Blood-brainbarrier(血脑屏障)Placentabarrier(胎盘屏障)Plasmaproteinbindingofdrug,2.Distribution:,Part2.Pharmacokineticsprocess,Plasmaproteinbindingrate(PBR,血浆蛋白结合率):FreetypeBindingtype,Freetype:Activity,Canbetransported.Bindingtype:Reversible;Inactivetemporarily;Cannotpassthroughcellmembranepassively;Saturabilityandcompetition.,Part2.Pharmacokineticsprocess,3.Biotransformation:,(1)Phaseofbiotransformation:Phase:Oxidation,Reduction,HydrolysisMostcase:inactivationordetoxificationSomecase:activationortoxicityactivation:cortisonehydrocortisonephenacetinacetaminophen(非那西丁)(对乙酰氨基酚)toxicity:para-phenetidin(对氨基苯乙醚),Part2.Pharmacokineticsprocess,Phase:Conjugation,withglucuronides,orglycine,oracetyl,orsulfate,etal.Resultofconjugation:Solubilityofcompoundseasytoexcretefromkidney.,Part2.Pharmacokineticsprocess,(2)Hepaticmicrosomalenzymes(肝微粒体酶,hepaticdrug-metabolizingenzymes,肝药酶),CytochromeP450enzymes(细胞色素P450),includingoxidases,reductases,hydrolasesandconjugases.,ThecharacteristicsofP450:lowselectivity(选择性低);highvariability(变异性大):481kinds;Enzymeinduction(酶诱导)andEnzymeinhibition(酶抑制).,Part2.Pharmacokineticsprocess,Enzymeinduction(酶诱导)2.persistentperiod(持续期);3.residualperiod(残留期),Part3.Therateprocessofpharmacokinetics,2.Kineticsofdrugelimination(药物消除动力学速率类型),dC=-keCndtC:concentration;t:time;ke:constantofeliminationrate.n=0:zero-orderkineticselimination.n=1:first-orderkineticselimination;,Part3.Therateprocessofpharmacokinetics,(1)Zero-orderelimination:(零级动力学消除,恒量消除),dCC=-k0C0dt=-k0dC=-k0dtCt=C0k0t0tConstantamountiseliminatedatmaximalcapacityperunittime;C-tcurveisastraightline,itsslopeis-k;tisnotconstant.,Part3.Therateprocessofpharmacokinetics,(2)First-orderkineticselimination:(一级动力学消除,恒比消除),dC=keC1dtdC=KeCdtdC=KedtCCt=C0e-ketlogCt=logC0ke/2.303t,Part3.Therateprocessofpharmacokinetics,t,0,t,0,slope=-ke/2.303,C,logC0,logC,logCt=logC0ke/2.303t,Part3.Therateprocessofpharmacokinetics,logCt=logC0-ke/2.303tt=2.303/ke(logC0-logCt)if:Ct=C0:t为半衰期t=2.303/kelog2=0.693/keke=0.693/tConstantfractioniseliminatedperunittime;logC-tcurveisastraightline,theslopeis-ke/2.303;t(半衰期)isconstant,=0.693/ke;(becontinued),Part3.Therateprocessofpharmacokinetics,onceinputdrug(A),after5t,96%ofAiseliminated.tsurplusage(%)elimination(%)0100.00150.050.0225.075.0312.587.546.2593.853.1296.961.5698.4,Part3.Therateprocessofpharmacokinetics,(3)Michaelis-Mentenelimination:e.g.:Phenytoin,Salicyclicacid,etal.,dCVmaxC=dtKm+CWhenCisveryhigh,KmC:零级动力学dCVmaxC=Vmax=K0dtCWhenCisverylow,KmC:一级动力学dCVmaxC=KeCdtKm,Part3.Therateprocessofpharmacokinetics,Michaelis-Mentenelimination(也称为非线性消除),Part3.Therateprocessofpharmacokinetics,3.Pharmacokineticsmodel(药动学模型),Compartmentmodel(房室模型),(1)one-compartmentmodel:,Drug,absorption,elimination,Part3.Therateprocessofpharmacokinetics,C=C0e-Ket,eliminationcurve,0123456t,one-compartmentmodel(iv),1,2,4,8,16,LogC,32,Part3.Therateprocessofpharmacokinetics,(2)two-compartmentmodel:,Drug,Centralcompartment,Peripheralcompartment,absorption,elimination,Part3.Therateprocessofpharmacokinetics,eliminationcurve,distributioncurve,C=Ae-t+Be-t,0,t,B,A,two-compartmentmodel(i.v.),logC,Part3.Therateprocessofpharmacokinetics,4.Parametersofpharmacokineticsandtheirmeanings:,(1)Areaundertheconentration-timecurve(AUC),(2)Bioavailability(F),(3)Apparentvolumeofdistribution(Vd),(4)Half-lifetime(t),Part3.Therateprocessofpharmacokinetics,(1)Areaundertheconentration-timecurve(AUC):,AUC代表药物进入体循环的相对量,可由梯形法则求得,AUC的单位用g/mlmin或mg/Lh表示.,AUC,Part3.Therateprocessofpharmacokinetics,(2)Bioavailability(生物利用度,F):,Fractionofabsorption(吸收分数),F=A/D100%,F=AUC(po)/AUC(iv)100%,F=AUC(供试药)/AUC(对照药)100%,Affectedfactors:,Rateofabsorption,Firstpasselimination(p.o.),Part3.Therateprocessofpharmacokinetics,某药剂量相等的三种制剂的生物利用度比较F(AUC)相等,但Tmax与Cmax不等,Part3.Therateprocessofpharmacokinetics,A(mg)Vd=(LorL/kg)C(mg/L)FDVdCVd=;D=CFVd5L:药物主要分布在血液中;Vd=1020L:分布在全身体液中;Vd40L:主要分布在组织器官中;Vd100L:集中分布在某个器官内.Vd值越小,排泄越快,体内存留时间越短;Vd值越大,排泄越慢,体内存留时间越长.,(3)Apparentvolumeofdistribution(表观分布容积,Vd):,Part3.Therateprocessofpharmacokinetics,First-orderkineticselimination:tisconstantt=0.693/ke,Part3.Therateprocessofpharmacokinetics,(4)Half-lifetime(半衰期,t):,t是血浆药物浓度或体内药量下降一半所需要的时间.,t的重要意义:,t表示药物在体内消除的速度或者机体对药物消除的能力,药物的t越长,则消除越慢;,若仅给药一次,并按一级动力学消除,则经过5个t体内96%以上的药物被消除;,同一类作用的药物可以按照其t长短再进行分类,例如长效类、中效类、短效类等;,肝、肾功能不良者,绝大多数药物t会延长.,Part3.Therateprocessofpharmacokinetics,logC,t,0,Cmax(峰浓度),Cmin(谷浓度),5.multipledosing(多次给药):,Steadystateconcentration(稳态浓度,Css,Plateau,坪值),Part3.Therateprocessofpharmacokinetics,t,0,logC,(1)Multipledosingrepeatedivinjection:,Part3.Therateprocessofpharmacokinetics,t,0,logC,(2)Changedoseandnotchangeinterval:,Part3.Therateprocessofpharmacokinetics,(3)Changedoseandinterval:,t,0,logC,Part3.Therateprocessofpharmacokinetics,(4)Loadingdose(DL):,t,0,D,2D,logC,2D=loadingdose,Part3.Therateprocessofpharmacokinetics,(5)Continuousivinjectionataconstantrate:,t,0,logC,Part3.Therateprocessofpharmacokinetics,Letstakearest!,Chapter2.Pharmacokinetics,Part1.DrugfactorsPart2.PatientfactorsPart3.Principleofrationaladministration,Section.PharmacologicalBasisofTherapeutics,Chapter3.Factorsinfluencingdrugeffect,(1)Injection:i.v.,i.m.,s.c.(2)Oraldosageform:Tablet;Powder;Capsule,Oralliquid.Bioequivalence(生物等效性)(3)Drugdeliverysystem(DDS):Slowreleaseform(缓释剂);Controlledreleaseform(控释剂):Extended(延迟)releaseform;Sustained(持续)releaseform.Transdermalpatch(透皮贴剂),1.Dosageform(剂型):,Part1.Drugfactors,Chapter3.Factorsinfluencingdrugeffect,(1)Dose(fromsmalldoselargedose);(2)Administrationroutes:iv,im,sc,po,inhalation,pr,etc.Absorptionrateandtakeeffecttime:ivinhalationimscpoprtransdermal.(3)Timeofadministration;(4)Intervalofadministration,t;(5)Courseoftreatment.,2.Methodsofadministration:,Part1.Drugfactors,(1)Drugincombination:Aimofdrugincombination:moreeffectivelytreatdisease.,(2)Drug-druginteraction(药物相互作用):,PharmaceuticalinteractionPhysicochemicalreactionincompatibility(配伍禁忌)PharmacokineticsinteractionPhar