Predicting the hepatic clearance of xenobiotics in humans from in vitro data
Predicting the hepatic clearance of xenobiotics in humans from in vitro data
复制标题
根据体外数据预测人类异生物质的肝脏清除率
DOI：
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发表时间：
1994
影响因子：
2.1
通讯作者：
B. Hoener
中科院分区：
文献类型：
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作者：
B. Hoener
通过细胞色素P450（P450）的特异性人同工酶将外源性生物质体外代谢为已知代谢物期间测定的Vmax和Km值用于预测外源性生物质对该代谢物的肝清除率（CLH）。然后将计算的CLH值与人体药代动力学研究期间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（P450 2 E1）的6-羟基化，预测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、利多卡因的脱乙基化（两项研究）和硝苯地平的氧化（均为P450 3A 3/4），数值分别为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。计算出利福平治疗后皮质醇至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 2D 6）的多态性。讨论了该方法的实用性及其局限性。
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 6β‐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 6β‐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.
细胞色素 P-450 催化 1,4-二氢吡啶脱氢。
DOI：
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发表时间：
1988
期刊：
The Journal of biological chemistry
影响因子：
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作者：
Guengerich,FP;Böcker,RH
通讯作者：
Böcker,RH