药科大生物药剂学课件第十一章 非线性药物动力学

LOGO简介线性药物动力学基本假定：体内吸收和配置过程符合一级动力学PKparameters(t1/2,CL)isindependentofDoseSizeand/ortimeAUCDoseSize,C(t)DoseSizeLinearPharmacokineticsDose-andtime-independentkineticsFirst-orderkineticsLOGO某些药物剂量或时间因素不符合线性药物动力学特点药物给药剂量(g)给药途径t1/2(h)水杨酸0.25iv2.41.30iv6.110~20iv19.1阿司匹林1.00po5.01.30po6.1LOGO(mg)AmountAbsorbed(mg)PercentofDoseAbsorbed0.50.4802.00.9455.01.326101.515502.042003.31.650061.1GastrointestinalAbsorptionofVitaminB12Adaptedfromthefigureonp.484,DocumentaGeigy,ScientificTables,7thEd.,1970LOGO(mg/mL)TimetoPeak(hrs)1000mg0.651500mg4.942000mg15.55Meansteady-statepharmacokineticparametersfromplasmaniacinLOGO(2):189-192NonlinearPharmacokineticsofMibefradilintheDogLOGOMichaelis-MentenEquationCkCVmmaxLOGOmaxVRateCkmmkCkmEquationatlowconcentrationskCCkVCkCmmmaxmaxVRateFirst-orderKineticsLOGOmaxVRateCkmCCkmEquationathighconcentrationsmaxmaxmaxVRateVCCVCkCmZero-orderKineticsLOGO(metabolism/transport)CkCmmaxVRate容量限制过程Saturationenzyme/carrier-mediatedAbsorption,Distribution,MetabolismandExcretionSaturationPlasmaprotein-DrugBindingEnzymeInduction,ProductInhibitionPathologicAlteration(s)inADME(aminoglycosidesrenalneprotoxicityrenaldrugexcretion)LOGO非线性(药物)动力学(可)饱和动力学容量限制性药物动力学剂量依赖性药物动力学NonlinearkineticsSaturablekineticsMichaelis-Mentionkinetics“Zero-order”kineticsCapacity-limitedkineticsDose-dependentkinetics/Time-dependentkineticsLOGO肠壁的饱和转运核黄素(VB2),VB12,L-dopaFB.药物相对不溶但剂量大灰黄霉素,ChorothiazideFC.肠壁或肝饱和首过效应Alprenolol,Lorcainid,烟酸,普奈洛尔,水杨酰胺FD.特殊吸收过程分布A.饱和的血浆蛋白结合保泰松,DisopyramideDisopyramide,华法令V,fuB.饱和的组织结合卡那霉素,硫喷妥,CyclosporinAVb,fuC.饱和的出入组织转运氨甲蝶呤(Methotrexate)D.CSF转运Benzylpenicillins具有非线性动力学特点的某些药物LOGOB.主动肾小管重吸收抗坏血酸,核黄素CLRC.尿液pH减小水杨酸CLRD.饱和的血浆蛋白结合DisopyramideCLRE.肾中毒(时间)氨基糖苷类CLRF.尿量增加(时间)茶碱CLR代谢A.酶容量限制的代谢苯妥因,茶碱,水杨酸CLHB.饱和的血浆蛋白结合氢化可的松CLRC.肝血流量减少普奈洛尔,VerapamilCLHD.酶诱导(时间)CarbamazepineCLHE.代谢物的抑制作用地西泮,LidocaineCLHF.肝中毒(时间)扑热息痛CLH胆汁A.胆汁分泌Iodipamide排泄B.肝肠循环CimetidineLOGO３.非线性药物动力学的特征Eliminationofdrugdoesn’tfollowsimplefirst-orderkinetics.Theeliminationhalf-lifechangesasdoseisincreased.TheAUCisnotproportionaltotheamountofbioavailabledrugThesaturationofcapacity-limitedprocessesmaybeaffectedbyotherdrugsthatrequirethesameenzymeorcarrier-mediatedsystem.ThecompositionofthemetabolitesofadrugmaybeaffectedbyachangeinthedoseLOGO静注(X0)体内药量(X)kel消除CkdtdXel-静注(X0)体内药量(X)Vmax,km消除CkCdtdXmmaxV-LOGOmaxV-CkCVmmaxdtVCkCdCmmax)(tVCCkCCmmax00ln)(LOGOmax00lnln)ln(100maxCCkCCVtmLOGOLOGOIfkmC0max02/12VCtLOGO~tp.oAUC~DoseSizePKModellingbasedonLinearPKDose/AUC~DoseSizeLOGO