米罗地尔及其代谢物 SK3541 在大鼠体内的药代动力学：CYP1A1/2、2B1/2、2D 亚家族和 3A1/2 参与米罗地尔和 SK3541 的代谢。

Pharmacokinetics of mirodenafil, a new erectogenic, and its metabolite, SK3541, in rats: involvement of CYP1A1/2, 2B1/2, 2D subfamily, and 3A1/2 for the metabolism of both mirodenafil and SK3541.

机构信息

College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea.

出版信息

J Pharm Pharm Sci. 2010;13(1):93-106. doi: 10.18433/j3688m.

DOI:10.18433/j3688m

PMID:20456834

Abstract

PURPOSE

This study was performed to find which types of hepatic CYP isoforms are responsible for the metabolism of mirodenafil (a new erectogenic) and one of its metabolite, SK3541, using various hepatic CYP inducers and inhibitors in rats.

METHODS

Mirodenafil at a dose of 20 mg/kg was administered intravenously to control rats and rats pretreated with various CYP inducers and inhibitors. The disappearance of SK3541 was also measured in vitro hepatic microsomes of rats with and without CYP inducer and inhibitors.

RESULTS

Compared to controls, in rats pretreated with 3-methylcholanthrene, orphenadrine, and dexamethasone (main inducers of CYP1A1/2, 2B1/2, and 3A1/2, respectively), the non-renal clearances (CLNRs) of mirodenafil were significantly faster (by 39.4%, 59.3%, and 63.9%, respectively). However, compared to controls, in rats pretreated with quinine and troleandomycin (main inhibitors of CYP2D subfamily and 3A1/2, respectively), the CLNRs of mirodenafil were significantly slower (by 36.1% and 33.2%, respectively). In rat hepatic microsomes spiked with furafylline, quinine, and troleandomycin (main inhibitors of CYP1A2, 2D subfamily, and 3A1/2, respectively), the intrinsic clearances (CLints) for the disappearance of SK3541 were significantly slower (by 18.4%, 35.3%, and 51.5%, respectively) than controls. Also in rat hepatic microsomes pretreated with orphenadrine (a main inducer of CYP2B1/2), the CLint for the disappearance of SK3541 was significantly faster (by 55.5%) than controls.

CONCLUSIONS

The above data suggest that hepatic CYP1A1/2, 2B1/2, 2D subfamily, and 3A1/2 are involved in the metabolism of both mirodenafil and SK3541 in rats.

摘要

目的

本研究旨在通过使用各种肝 CYP 诱导剂和抑制剂在大鼠中，寻找负责米罗地尔（一种新型勃起功能障碍药物）及其代谢物 SK3541 代谢的肝 CYP 同工酶的类型。

方法

以 20mg/kg 的剂量静脉给予对照大鼠和用各种 CYP 诱导剂和抑制剂预处理的大鼠米罗地尔。还测量了有和没有 CYP 诱导剂和抑制剂的大鼠肝微粒体中 SK3541 的体外消失情况。

结果

与对照组相比，用 3-甲基胆蒽、安非他酮和地塞米松（分别为 CYP1A1/2、2B1/2 和 3A1/2 的主要诱导剂）预处理的大鼠中，米罗地尔的非肾清除率（CLNR）明显加快（分别加快 39.4%、59.3%和 63.9%）。然而，与对照组相比，用奎尼丁和曲利本胺（分别为 CYP2D 亚家族和 3A1/2 的主要抑制剂）预处理的大鼠中，米罗地尔的 CLNR 明显减慢（分别减慢 36.1%和 33.2%）。在加入了呋喃西林、奎尼丁和曲利本胺（分别为 CYP1A2、2D 亚家族和 3A1/2 的主要抑制剂）的大鼠肝微粒体中，SK3541 消失的内在清除率（CLint）明显减慢（分别减慢 18.4%、35.3%和 51.5%）。在安非他酮（CYP2B1/2 的主要诱导剂）预处理的大鼠肝微粒体中，SK3541 消失的 CLint 明显加快（加快 55.5%）。