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首页> 外文期刊>Journal of pharmaceutical sciences. >Hepatic disposition of the cytochrome P450 2E1 marker chlorzoxazone and its hydroxylated metabolite in isolated perfused rat livers.
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Hepatic disposition of the cytochrome P450 2E1 marker chlorzoxazone and its hydroxylated metabolite in isolated perfused rat livers.

机译：细胞色素P450 2E1标记氯唑沙宗及其羟基化代谢产物在离体灌流大鼠肝脏中的肝脏处置。

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摘要

The steady-state disposition of chlorzoxazone (CZX) and its hydroxylated metabolite 6-hydroxychlorzoxazone (HCZX) was determined in a single-pass isolated perfused rat liver (IPRL) model using constant CZX concentrations of 10-200 microM. The concentrations of CZX, HCZX, and/or HCZX glucuronide in the perfusate, bile, and liver tissues were measured and kinetic parameters calculated. Upon an increase in CZX inlet concentrations from 10 to 200 microM, its extraction ratio sharply declined from 0.681 to 0.087. This was associated with a saturable formation of HCZX, which was rapidly and completely metabolized to its glucuronide conjugate. Whereas the biliary excretion of CZX was negligible, that of HCZX was substantial (up to 40% of the generated metabolite). Overall, 79-93% of the CZX dose (10-200 microM) was recovered in our model as CZX and HCZX. Additionally, HCZX accounted for 56% (200 microM) to 71% (10 microM) of the extracted CZX dose. Further, a preliminary study using the preformed HCZX showed a complete (100%) recovery of the metabolite as its conjugate. Therefore, the unrecovered portion of CZX dose in our study (7-21% of the administered dose or 29-44% of the extracted dose at inlet CZX concentrations of 10-200 microM) is most likely due to parallel metabolism of CZX to other metabolites. (c) 2006 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 95: 1414-1424, 2006.
机译：氯唑沙宗（CZX）及其羟基化代谢物6-羟基氯唑沙宗（HCZX）的稳态处置是在10-200 microM恒定CZX浓度的单次分离灌流大鼠肝脏（IPRL）模型中确定的。测量灌注液，胆汁和肝组织中CZX，HCZX和/或HCZX葡糖醛酸的浓度，并计算动力学参数。当CZX入口浓度从10 microM增加到200 microM时，其提取率从0.681急剧下降到0.087。这与HCZX的饱和形成有关，该HCZX被迅速且完全代谢成其葡糖醛酸苷结合物。尽管CZX的胆汁排泄量可以忽略不计，但HCZX的胆汁排泄量却很大（最多占所生成代谢物的40％）。总体而言，在我们的模型中CZX和HCZX回收了79-93％的CZX剂量（10-200 microM）。另外，HCZX占提取的CZX剂量的56％（200 microM）至71％（10 microM）。此外，使用预制的HCZX进行的初步研究表明，代谢物作为其结合物可以完全（100％）回收。因此，在我们的研究中，未回收的CZX剂量（在进口CZX浓度为10-200 microM时，占给药剂量的7-21％或提取剂量的29-44％）最可能是由于CZX与其他药物平行代谢代谢产物。 （c）2006 Wiley-Liss，Inc.和美国药剂师协会J Pharm Sci 95：1414-1424，2006。

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