藥科大生物藥劑學第十一章 非線性藥物動力學課件

1、Bo WangAssociate Professor of PharmaceuticsDepartment of PharmaceuticsChina Pharmaceutical UniversityLOGO第十一章 非線性藥物動力學1.簡介線性藥物動力學基本假定：體內(nèi)吸收和配置過程符合一級動力學PK parameters (t1/2, CL) is independent of Dose Size and/or timeAUC Dose Size, C(t) Dose SizeLinear PharmacokineticsDose- and time-independent kinetic

2、sFirst-order kineticsLOGO某些藥物劑量或時間因素不符合線性藥物動力學特點藥物給藥劑量(g)給藥途徑t1/2 (h)水楊酸0.25iv2.41.30iv6.110 20iv19.1阿司匹林1.00po5.01.30po6.1LOGODose (mg) Amount Absorbed (mg) Percent of Dose Absorbed 0.5 0.4802.00.9455.01.326101.515502.042003.31.650061.1Gastrointestinal Absorption of Vitamin B12Adapted from the figu

3、re on p. 484, Documenta Geigy, Scientific Tables, 7th Ed., 1970LOGODose/day Peak Conc (mg/mL) Time to Peak (hrs) 1000 mg0.651500 mg4.942000 mg15.55Mean steady-state pharmacokinetic parameters from plasma niacin LOGOLOGOLOGOJournal of Pharmaceutical Sciences. 1996, 85(2): 189-192Nonlinear Pharmacokin

4、etics of Mibefradil in the DogLOGOLOGOLOGOEquation at low concentrationsFirst-order KineticsLOGOEquation at high concentrationsZero-order KineticsLOGOLOGOCapacity-limited process (metabolism/transport)容量限制過程 Saturation enzyme/carrier-mediated Absorption, Distribution, Metabolism and Excretion Satura

5、tion Plasma protein-Drug Binding Enzyme Induction, Product Inhibition Pathologic Alteration(s) in ADME (aminoglycosides renal neprotoxicity renal drug excretion)LOGO非線性(藥物)動力學(可)飽和動力學容量限制性藥物動力學劑量依賴性藥物動力學Nonlinear kineticsSaturable kineticsMichaelis-Mention kinetics“Zero-order” kineticsCapacity-limit

6、ed kineticsDose-dependent kinetics/Time-dependent kineticsLOGO階段相關(guān)原因案例參數(shù)變化吸收A. 腸壁的飽和轉(zhuǎn)運核黃素(VB2),VB12,L-dopaF B. 藥物相對不溶但劑量大灰黃霉素,ChorothiazideF C. 腸壁或肝飽和首過效應(yīng)Alprenolol, Lorcainid,煙酸,普奈洛爾,水楊酰胺F D. 特殊吸收過程分布A. 飽和的血漿蛋白結(jié)合保泰松, Disopyramide Disopyramide, 華法令V, fu B. 飽和的組織結(jié)合卡那霉素,硫噴妥,Cyclosporin AVb, fu C. 飽和的出

7、入組織轉(zhuǎn)運氨甲蝶呤(Methotrexate)D. CSF轉(zhuǎn)運Benzylpenicillins具有非線性動力學特點的某些藥物LOGO階段相關(guān)原因案例參數(shù)變化排泄A. 主動腎小管分泌青霉素G, PAACLR B. 主動腎小管重吸收抗壞血酸,核黃素CLR C. 尿液pH減小水楊酸CLR D. 飽和的血漿蛋白結(jié)合DisopyramideCLR E. 腎中毒(時間)氨基糖苷類CLR F. 尿量增加(時間)茶堿CLR 代謝A. 酶容量限制的代謝苯妥因,茶堿,水楊酸CLH B. 飽和的血漿蛋白結(jié)合氫化可的松CLR C. 肝血流量減少普奈洛爾, VerapamilCLH D. 酶誘導(時間)CarbamazepineCLH E. 代謝物的抑制作用地西泮, LidocaineCLH F. 肝中毒(時間)撲熱息痛CLH 膽汁A. 膽汁分泌Iodipamide排泄B. 肝腸循環(huán)CimetidineLOGO靜注(X0)體內(nèi)藥量(X)kel消除靜注(X0)體內(nèi)藥量(X)Vmax, km消除LOGOLOGOLOGOLOGO4.非線性藥物動力學方程Michaelis-Menten Enzymatic KineticsL