Formation of 4'-carboxyl acid metabolite of imrecoxib by rat liver microsomes  

作　　者：Hai-yan XU Peng ZHANG Ai-shen GONG Yu-ming SUN Feng-ming CHU Zong-m GUO Da-fang ZHONG 

机构地区：[1]Laboratory of Drug Metabolism and Pharmacokinetics, Shenyang Pharmaceutical University, Shenyang 110016, China [2]Research and Development Center, Shanghai Hengrui Pharmaceutical Co, Shanghai 200245, China [3]Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China [4]Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China

出　　处：《Acta Pharmacologica Sinica》2006年第4期506-512,共7页中国药理学报（英文版）

基　　金：Project supported by the National High Technology Research and Development Program of China(№2003AA2Z347C).

摘　　要：Aim： Imrecoxib is a novel and moderately selective COX-2 inhibitor. The aim of the present in vitro investigation was to study the formation of the major metabolite 4^1-carboxylic acid imrecoxib （M2） and identify the enzyme（s） involved in the reaction. Methods： The formation of M2 was studied in rat liver cytosol in the absence or presence of liver microsomes. The formed metabolite was identified and quantified by LC/MSn. In addition, to characterize the cytochrome P450 （CYP） isozymes involved in M2 formation, the effects of typical CYP inhibitors （such as ketoconazle, quinine, α-naphthoflavone, methylpyrazole, and cimetidine） on the formation rate of M2 were investigated. Results： The formation of M2 from 4^1- hydroxymethyl imrecoxib （M4） was completely dependent on rat liver microsomes and NADPH. Enzyme kinetic studies demonstrated that the formation rate of M2 conformed to monophasic Michaelis-Menten kinetics. Additional experiments showed that the formation of M2 was induced significantly by dexamethasone and lowered by ketoconazole strongly and concentration-dependently. By comparison, other CYP inhibitors, such as α-naphthoflavone, cimetidine, quinine, and methylpyrazole had no inhibitory effects on this metabolic pathway. Conclusion： These biotransformation studies of M4 and imrecoxib in rat liver at the subcellular level showed that the formation of M2 occurs in rat liver microsomes and is NADPH-dependent. The reaction was mainly catalyzed by CYP 3A in untreated rats and in dexamethasone-induced rats. Other CYP, such as CYP IA, 2C, 2D, and 2E, seem unlikely to participate in this metabolic pathway.Aim： Imrecoxib is a novel and moderately selective COX-2 inhibitor. The aim of the present in vitro investigation was to study the formation of the major metabolite 4^1-carboxylic acid imrecoxib （M2） and identify the enzyme（s） involved in the reaction. Methods： The formation of M2 was studied in rat liver cytosol in the absence or presence of liver microsomes. The formed metabolite was identified and quantified by LC/MSn. In addition, to characterize the cytochrome P450 （CYP） isozymes involved in M2 formation, the effects of typical CYP inhibitors （such as ketoconazle, quinine, α-naphthoflavone, methylpyrazole, and cimetidine） on the formation rate of M2 were investigated. Results： The formation of M2 from 4^1- hydroxymethyl imrecoxib （M4） was completely dependent on rat liver microsomes and NADPH. Enzyme kinetic studies demonstrated that the formation rate of M2 conformed to monophasic Michaelis-Menten kinetics. Additional experiments showed that the formation of M2 was induced significantly by dexamethasone and lowered by ketoconazole strongly and concentration-dependently. By comparison, other CYP inhibitors, such as α-naphthoflavone, cimetidine, quinine, and methylpyrazole had no inhibitory effects on this metabolic pathway. Conclusion： These biotransformation studies of M4 and imrecoxib in rat liver at the subcellular level showed that the formation of M2 occurs in rat liver microsomes and is NADPH-dependent. The reaction was mainly catalyzed by CYP 3A in untreated rats and in dexamethasone-induced rats. Other CYP, such as CYP IA, 2C, 2D, and 2E, seem unlikely to participate in this metabolic pathway.

关 键 词：IMRECOXIB cytochrome P450 METABOLISM liver microsomes RATS 

分 类 号：R575[医药卫生—消化系统]