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

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	Role of rat liver cytochrome P450 3A and 2D in metabolism of imrecoxib
其他题名	Role of rat liver cytochrome P450 3A and 2D in metabolism of imrecoxib
	Xu HY 1; Xie ZY 1; Zhang P 1; Sun J 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:3 页码:372-380
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 beta-naphthoflavone) and of CYP inhibitors (such as ketoconazole, quinine, alpha-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-car-bonyl imrecoxib (M5). Over the imrecoxib concentration range studied (5-600 mu mol/L), the rate of 4'-methyl hydroxylation conformed to monophasic Michaelis-Menten 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 beta-naphthoflavone-induced rats. In contrast, alpha-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 3 A. CYP 2D also played a role in control rats, in isoniazid-induced rats and in beta-naphthoflavone-induced rats.
其他摘要	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.
关键词	NONSTEROIDAL ANTIINFLAMMATORY DRUGS COX-2 INHIBITORS IN-VITRO MICROSOMES CYCLOOXYGENASE-2 OSTEOARTHRITIS ISOENZYMES NSAIDS VIVO imrecoxib cytochrome P450 metabolism liver microsomes
收录类别	CSCD
语种	英语
CSCD记录号	CSCD:2621336
引用统计	被引频次：1[CSCD] [CSCD记录]
文献类型	期刊论文
条目标识符	http://ir.imr.ac.cn/handle/321006/143851
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.中国科学院 3.Peking Union Med Coll
推荐引用方式 GB/T 7714	Xu HY,Xie ZY,Zhang P,et al. Role of rat liver cytochrome P450 3A and 2D in metabolism of imrecoxib[J]. ACTA PHARMACOLOGICA SINICA,2006,27(3):372-380.
APA	Xu HY.,Xie ZY.,Zhang P.,Sun J.,Chu FM.,...&Zhong DF.(2006).Role of rat liver cytochrome P450 3A and 2D in metabolism of imrecoxib.ACTA PHARMACOLOGICA SINICA,27(3),372-380.
MLA	Xu HY,et al."Role of rat liver cytochrome P450 3A and 2D in metabolism of imrecoxib".ACTA PHARMACOLOGICA SINICA 27.3(2006):372-380.