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

作　　者：Hai-yan XU Zhi-yong XIE Peng ZHANG Jin SUN Feng-ming cno Zong-ru GUO Da-fang ZHONG 

机构地区：[1]Laboratory of Drug Metabolism and Pharmacokinetics [2]Department of Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang110016, China [3]Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050,China

出　　处：《Acta Pharmacologica Sinica》2006年第3期372-380,共9页中国药理学报（英文版）

基　　金：Project supported by a grant from the "863"program of China(№2003AA2Z347C).

摘　　要：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.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.

关 键 词：IMRECOXIB cytochrome P450 METABOLISM liver microsomes 

分 类 号：R575[医药卫生—消化系统]