Poor correlation between intestinal and hepatic metabolic rates of CYP3A4 substrates in rats
Poor correlation between intestinal and hepatic metabolic rates of CYP3A4 substrates in rats
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DOI：
10.1023/a:1023429401738
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发表时间：
2003-05-01
影响因子：
3.7
通讯作者：
Hashimoto, Y
中科院分区：
文献类型：
--
作者：
Aiba, T;Takehara, Y;Hashimoto, Y
目的。为了阐明肠道首过代谢对药物生物利用度的贡献，研究了人CYP3A4底物在大鼠体内的肠道代谢和肝脏代谢的相关性。4种化合物(利多卡因、奎尼丁、硝苯地平和利福平)的代谢率用离体肠组织和肝微粒体进行检测。用免疫印迹法检测细胞色素P3A1/23和细胞色素P3A2在肠道和肝脏中的表达。利福布汀在离体肠组织中代谢最快，利多卡因代谢最慢。相比之下，利多卡因在肝微粒体中代谢最快，利福布丁最慢。利多卡因的肝脏代谢可被CYP2D6底物地昔帕明抑制，而不是被CYP3A4抑制剂酮康唑抑制。此外，CYP3A亚家族成员在肠道中的表达与在肝脏中的表达不同。人CYP3A4底物在大鼠体内的肠道和肝脏代谢相关性较差，可能是由于CYP2D亚家族对肝脏药物代谢的贡献，也可能是由于CYP3A亚家族在肠道中的独特表达。
Purpose. To clarify the contribution of the intestinal first-pass metabolism to the drug bioavailability, the correlation between the intestinal and hepatic metabolism of human CYP3A4 substrates was investigated in rats.Methods. The metabolic rates of four compounds ( lidocaine, quinidine, nifedidpine, and rifabutin) were examined with excised intestinal tissues and liver microsomes. The intestinal and hepatic expression of CYP3A1/23 and CYP3A2 was evaluated by Western blot analysis.Results. Rifabutin was metabolized fastest, and lidocaine was metabolized slowest in excised intestinal tissues. By contrast, lidocaine was metabolized fastest and rifabutin was the slowest in liver microsomes. The hepatic metabolism of lidocaine was inhibited by a CYP2D6 substrate desipramine, not by a CYP3A4 inhibitor ketoconazole. In addition, members of the CYP3A subfamily expressed in the intestine were different from those expressed in the liver.Conclusions. Poor correlation between the intestinal and hepatic metabolism of human CYP3A4 substrates in rats may be caused by the contribution of the CYP2D subfamily to the drug metabolisms in the liver and also by the unique expression of the CYP3A subfamily in the intestine.