药科大生物药剂学课件第十一章 非线性药物动力学.pptVIP

第十一章 非线性药物动力学 ３.非线性药物动力学的特征 Elimination of drug doesn’t follow simple first-order kinetics . The elimination half-life changes as dose is increased. The AUC is not proportional to the amount of bioavailable drug The saturation of capacity-limited processes may be affected by other drugs that require the same enzyme or carrier- mediated system. The composition of the metabolites of a drug may be affected by a change in the dose 静注 (X0) 体内药量 (X) kel 消除 静注 (X0) 体内药量 (X) Vmax, km 消除 4.非线性药物动力学方程 Michaelis-Menten Enzymatic Kinetics LOGO * CPU * CPU * CPU * CPU * Bo Wang Associate Professor of Pharmaceutics Department of Pharmaceutics China Pharmaceutical University 1.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 PK parameters (t1/2, CL) is independent of Dose Size and/or time AUC ? Dose Size, C(t) ? Dose Size Linear Pharmacokinetics Dose- and time-independent kinetics First-order kinetics 某些药物 剂量或时间因素 不符合线性药物动力学特点 6.1 po 1.30 5.0 po 1.00 阿司匹林 19.1 iv 10 ~ 20 6.1 iv 1.30 2.4 iv 0.25 水杨酸 t1/2 (h) 给药途径 给药剂量(g) 药物 1.1 6 500 1.6 3.3 200 4 2.0 50 15 1.5 10 26 1.3 5.0 45 0.9 2.0 80 0.4 0.5 Percent of Dose Absorbed Amount Absorbed (mg) Dose (mg) Gastrointestinal Absorption of Vitamin B12 Adapted from the figure on p. 484, Documenta Geigy, Scientific Tables, 7th Ed., 1970 5 0.6 1000 mg 5 15.5 2000 mg 4 4.9 1500 mg Time to Peak (hrs) Peak Conc (mg/mL) Dose/day Mean steady-state pharmacokinetic parameters from plasma niacin Journal of Pharmaceutical Sciences. 1996, 85(2): 189-192 Nonlinear Pharmacokinetics of Mibefradil in the Dog 2.出现非线性药物动力学的原因 代谢或转运过程 Michaelis-Menten Equation Equation at low concentrations First-order Kinetics Equation at high concentrations Zero-order Kinetics Capacity-limited process (metabolism/transport) 容量限制过程 Saturation ? enzyme/carrier-mediated Absorption, Distribution, Metabolism and Excretion Saturation ? Plasma protein-Drug Binding Enzyme Induction, Product Inhibition Pathologic Alteration(s) in ADME (aminoglycosides ? renal