药科大生物药剂学课件第十一章 非线性药物动力学.pptVIP

LOGO 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 LOGO CPU CPU CPU CPU Bo Wang Associate Professor of Pharmaceutics Department of Pharmaceutics China Pharmaceutical University 第十一章 非线性药物动力学 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 药物 给药剂量(g) 给药途径 t1/2 (h) 水杨酸 0.25 iv 2.4 1.30 iv 6.1 10 ~ 20 iv 19.1 阿司匹林 1.00 po 5.0 1.30 po 6.1 Dose (mg) Amount Absorbed (mg) Percent of Dose Absorbed 0.5 0.4 80 2.0 0.9 45 5.0 1.3 26 10 1.5 15 50 2.0 4 200 3.3 1.6 500 6 1.1 Gastrointestinal Absorption of Vitamin B12 Adapted from the figure on p. 484, Documenta Geigy, Scientific Tables, 7th Ed., 1970 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 neprotoxicity ? renal drug excretion) 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 Nonlinear kinetics Saturable kinetics Michaelis-Mention kinetics “Zero-order” kinetics Capacity-limited kinetics Dose-depen