药剂学课件：第十一章 非线性药物动力学.pptVIP

LOGO 静注 (X0) 体内药量 (X) kel 消除 静注 (X0) 体内药量 (X) Vmax, km 消除 LOGO LOGO LOGO LOGO LOGO 4.非线性药物动力学方程 Michaelis-Menten Enzymatic Kinetics LOGO LOGO LOGO If km C0 If km C0 LOGO 5.非线性药物动力学的识别 i.v 3 dose sizes Conc/AUC ~ t p.o AUC ~ Dose Size PK Modelling based on Linear PK Dose /AUC ~ Dose Size LOGO LOGO CPU CPU CPU CPU 第十一章 非线性药物动力学 LOGO 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 LOGO 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 LOGO 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 LOGO LOGO Dose/day Peak Conc (mg/mL) Time to Peak (hrs) 1000 mg 0.6 5 1500 mg 4.9 4 2000 mg 15.5 5 Mean steady-state pharmacokinetic parameters from plasma niacin LOGO LOGO LOGO LOGO Journal of Pharmaceutical Sciences. 1996, 85(2): 189-192 Nonlinear Pharmacokinetics of Mibefradil in the Dog LOGO LOGO 2.出现非线性药物动力学的原因 代谢或转运过程 Michaelis-Menten Equation LOGO LOGO Equation at low concentrations First-order Kinetics LOGO LOGO Equation at high concentrations Zero-order Kinetics LOGO LOGO 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) 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 Nonlinear kinetics Saturable kinetics Michaelis-Mention kinetics “Zero-order” kinetics Capacity-limited kinetics Dose-dependent kinetics/Time-dependent k