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

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	Formation of 4 '-carboxyl acid metabolite of imrecoxib by rat liver microsomes
其他题名	Formation of 4′-carboxyl acid metabolite of imrecoxib by rat liver microsomes
	Xu HY 1; Zhang P 1; Gong AS 1; Sun YM 1; Chu FM 1; Guo ZR 1; Zhong DF 1
	2006
发表期刊	ACTA PHARMACOLOGICA SINICA
ISSN	1671-4083
卷号	27 期号:4 页码:506-512
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'-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, alpha-naphthoflavone, methylpyrazole, and cimetidine) on the formation rate of M2 were investigated. Results: The formation of M2 from 4'-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 alpha-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 3 A in untreated rats and in dexamethasone-induced rats. Other CYP, such as CYP 1 A, 2C, 2D, and 2E, seem unlikely to participate in this metabolic pathway.
其他摘要	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.
关键词	PRIMARY CULTURES CYCLOOXYGENASE-2 HEPATOCYTES INDUCTION imrecoxib cytochrome P450 metabolism liver microsomes rats
收录类别	CSCD
语种	英语
CSCD记录号	CSCD:2462105
引用统计
文献类型	期刊论文
条目标识符	http://ir.imr.ac.cn/handle/321006/158139
专题	中国科学院金属研究所
作者单位	1.中国科学院金属研究所 2.Shanghai Hengrui Pharmaceut Co 3.中国科学院 4.Peking Union Med Coll 5.中国科学院
推荐引用方式 GB/T 7714	Xu HY,Zhang P,Gong AS,et al. Formation of 4 '-carboxyl acid metabolite of imrecoxib by rat liver microsomes[J]. ACTA PHARMACOLOGICA SINICA,2006,27(4):506-512.
APA	Xu HY.,Zhang P.,Gong AS.,Sun YM.,Chu FM.,...&Zhong DF.(2006).Formation of 4 '-carboxyl acid metabolite of imrecoxib by rat liver microsomes.ACTA PHARMACOLOGICA SINICA,27(4),506-512.
MLA	Xu HY,et al."Formation of 4 '-carboxyl acid metabolite of imrecoxib by rat liver microsomes".ACTA PHARMACOLOGICA SINICA 27.4(2006):506-512.