药剂学课件：第十一章 非线性药物动力学

第十一章非线性药物动力学LOGO1.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1.00po5.01.30po6.1LOGODose(mg)

AmountAbsorbed(mg)

PercentofDoseAbsorbed

0.50.4802.00.9455.01.326101.515502.042003.31.650061.1GastrointestinalAbsorptionofVitaminB12Adaptedfromthefigureonp.484,DocumentaGeigy,ScientificTables,7thEd.,1970LOGOLOGODose/day

PeakConc(mg/mL)

TimetoPeak(hrs)

1000mg0.651500mg4.942000mg15.55Meansteady-statepharmacokineticparametersfromplasmaniacinLOGOLOGOLOGOLOGOJournalofPharmaceuticalSciences.1996,85(2):189-192NonlinearPharmacokineticsofMibefradilintheDogLOGOLOGO2.出现非线性药物动力学的原因代谢或转运过程Michaelis-MentenEquationLOGOLOGOEquationatlowconcentrationsFirst-orderKineticsLOGOLOGOEquationathighconcentrationsZero-orderKineticsLOGOLOGOCapacity-limitedprocess(metabolism/transport)容量限制过程Saturation

enzyme/carrier-mediatedAbsorption,Distribution,MetabolismandExcretionSaturationPlasmaprotein-DrugBindingEnzymeInduction,ProductInhibitionPathologicAlteration(s)inADME(aminoglycosidesrenalneprotoxicityrenaldrugexcretion)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-limitedkinetics Dose-dependentkinetics/Time-dependentkineticsLOGO阶段相关原因案例参数变化吸收A.

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阶段相关原因案例参数变化排泄A.主动肾小管分泌青霉素G,PAACLR

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.TheAUCisnotproportionaltotheamountofbioavailabledrugThesaturationofcapacity-limitedprocessesmaybeaffectedbyotherdrugsthatrequirethesameenzymeorcarrier-mediatedsystem.ThecompositionofthemetabolitesofadrugmaybeaffectedbyachangeinthedoseLOGO静注(X0)体内药量(X)kel消除静注(X0)体内药量(X)Vmax,km消除LOGOLOGOLOGOLOGOLOGO4.非线性药物动力学方程Michaelis-MentenEnzymaticKineticsLOGOLOGOLOGOI