Keller F
Medical Department, University Hospital Ulm, Germany.
Clin Nephrol. 1995 Jan;43 Suppl 1:S24-6.
An equation for saturable nonlinear first-pass kinetics is presented to discuss some contra-intuitive findings encountered with furosemide bioavailability. The diverging effects on steady-state bioavailability (Fss) are simulated for changes in maximal metabolic capacity (Vm), volume of distribution (Vd), Michaelis constant (Km), steady-state plasma concentration (Css), repetitively administered drug dose (Dss), dosage interval (Tau), liver plasma flow (Ql), absorption rate constant (Ka), and free plasma fraction (fp), where (Cssf = fp Css = const.) and (Kmf = fp Km = const.). [Formula: see text] The present concept is in line with observations indicating that furosemide bioavailability decreases from 60 to 45% in nephrotic syndrome patients whose plasma protein binding is reduced and hepatic clearance increased. These observations and our equation-based simulations show that furosemide must have a first-pass effect. Hepatic extraction of furosemide is not facilitated by albumin, and saturable first-pass kinetics can not be used to explain an albumin paradox.
提出了一个关于可饱和非线性首过动力学的方程，以讨论速尿生物利用度中遇到的一些违反直觉的发现。针对最大代谢能力（Vm）、分布容积（Vd）、米氏常数（Km）、稳态血浆浓度（Css）、重复给药剂量（Dss）、给药间隔（Tau）、肝血浆流量（Ql）、吸收速率常数（Ka）和游离血浆分数（fp）的变化，模拟了对稳态生物利用度（Fss）的不同影响，其中（Cssf = fp Css = 常数）且（Kmf = fp Km = 常数）。[公式：见原文] 目前的概念与观察结果一致，这些观察结果表明，在血浆蛋白结合降低且肝清除率增加的肾病综合征患者中，速尿的生物利用度从60%降至45%。这些观察结果以及我们基于方程的模拟表明，速尿必定具有首过效应。白蛋白无助于速尿的肝摄取，且可饱和首过动力学无法用于解释白蛋白悖论。
