从体外数据预测人体中外源物质的肝清除率。
Predicting the hepatic clearance of xenobiotics in humans from in vitro data.
作者信息
Hoener B A
机构信息
Department of Pharmacy, School of Pharmacy, University of California, San Francisco 94143-0446.
出版信息
Biopharm Drug Dispos. 1994 May;15(4):295-304. doi: 10.1002/bdd.2510150404.
Values for Vmax and Km determined during the in vitro metabolism of a xenobiotic to a known metabolite by a specific human isozyme of cytochrome P450 (P450) were used to predict the hepatic clearance (CLH) of the xenobiotic to that metabolite. The calculated CLH values were then compared to literature values of clearance (CL) to the same metabolite obtained during pharmacokinetic studies in humans. For the 6-hydroxylation of chlorzoxazone (P450 2E1) the predicted and actual clearances were 110 +/- 77 mL min-1 and 110 mL min-1, respectively. For the 6 beta-hydroxylation of cortisol, the deethylation of lidocaine (two studies), and the oxidation of nifedipine (all P450 3A3/4) the values were 13 +/- 15 mL min-1 and 13 mL min-1; 758 +/- 282 or 829 +/- 283 mL min-1 and 875 mL min-1; and 284 +/- 176 mL min-1 and 294 mL min-1, respectively. An increase to 72 +/- 25 mL min-1 in the CLH of cortisol to 6 beta-hydroxycortisol was calculated following rifampicin treatment. Finally, the polymorphic nature of the metabolism (P450 2D6) of mexiletine was confirmed. The usefulness of the method and its limitations are discussed.
通过细胞色素P450（P450）的特定人类同工酶将外源性物质体外代谢为已知代谢物的过程中所测定的Vmax和Km值，被用于预测该外源性物质向该代谢物的肝脏清除率（CLH）。然后将计算得出的CLH值与人类药代动力学研究中获得的相同代谢物的清除率（CL）文献值进行比较。对于氯唑沙宗的6-羟基化反应（P450 2E1），预测清除率和实际清除率分别为110±77 mL min⁻¹和110 mL min⁻¹。对于皮质醇的6β-羟基化反应、利多卡因的脱乙基反应（两项研究）以及硝苯地平的氧化反应（均为P450 3A3/4），相应的值分别为13±15 mL min⁻¹和13 mL min⁻¹；758±282或829±283 mL min⁻¹和875 mL min⁻¹；以及284±176 mL min⁻¹和294 mL min⁻¹。经利福平治疗后，计算得出皮质醇向6β-羟基皮质醇的CLH增加至72±25 mL min⁻¹。最后，证实了美西律代谢（P450 2D6）的多态性。讨论了该方法的实用性及其局限性。
Zotero 插件