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Role of rat liver cytochrome P450 3A and 2D in metabolism of imrecoxib

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文摘 Aim： To investigate the in vitro metabolism of imrecoxib in rat liver microsomes and to identify the cytochrome P450 （CYP） forms involved in its metabolism. Methods： Liver microsomes of Wistar rats were prepared using an ultracentrifuge, The in vitro metabolism of imrecoxib was studied by incubation with rat liver microsomes. To characterize the CYP forms involved in the 4＇-methyl hydroxylation of imrecoxib, the effects of typical CYP inducers （such as dexamethasone, isoniazid and β-naphthoflavone） and of CYP inhibitors （such as ketoconazole, quinine, α-naphthoflavone, methylpyrazole, and cimetidine） on the formation rate of 4＇-hydroxymethyl imrecoxib were investigated. Results： Imrecoxib was metabolized to 3 metabolites by rat liver microsomes： 4＇-hydroxymethyl imrecoxib （M4）, 4＇-hydroxymethyl-5-hydoxyl imrecoxib （M3）, and 4＇-hydroxymethyl-5-carbonyl imrecoxib （M5）. Over the imrecoxib concentration range studied （5-600 μmol/L）, the rate of 4＇-methyl hydroxylation conformed to monophasic MichaelisMenten kinetics. Dexamethasone significantly induced the formation of M4. Ketoconazole markedly lowered the metabolic rate of imrecoxib in a concentration-dependent manner. Moreover, a significant inhibitory effect of quinine on the formation of M4 was observed in microsomes obtained from control rats, isoniazid-induced rats, and β-naphthoflavone-induced rats. In contrast, α- naphthoflavone, cimetidine, and methylpyrazole had no inhibitory effects on this metabolic pathway. Conclusion： Imrecoxib is metabolized via 4＇-methyl hydroxylation in rat liver microsomes. The reaction is mainly catalyzed by CYP 3A. CYP 2D also played a role in control rats, in isoniazid-induced rats and in β- naphthoflavone-induced rats.
来源 Acta Pharmacologica Sinica ,2006,27(3):372-380 【核心库】
DOI 10.1111/j.1745-7254.2006.00265.x
关键词 imrecoxib ; cytochrome P450 ; metabolism ; liver microsomes
地址

1. Laboratory of Drug Metabolism and Pharmacokinetics, Shenyang Pharmaceutical University, Shenyang, 110016  

2. Department of Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, 110016  

3. Institute of Materia Medica，Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050

语种 英文
文献类型 研究性论文
ISSN 1671-4083
学科 内科学
基金 国家863计划
文献收藏号 CSCD:2621336

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1 郭宗儒 国家1类新药艾瑞昔布的研制 中国新药杂志,2012,21(3):223-230
被引 5 次

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