Formation of 4 '-carboxyl acid metabolite of imrecoxib by rat liver microsomes
文献类型：期刊论文
| 作者 | Xu HY1; Zhang P1; Gong AS1; Sun YM1; Chu FM1; Guo ZR1; Zhong DF1 |
| 刊名 | ACTA PHARMACOLOGICA SINICA
 |
| 出版日期 | 2006 |
| 卷号 | 27期号:4页码:506-512 |
| 关键词 | PRIMARY CULTURES CYCLOOXYGENASE-2 HEPATOCYTES INDUCTION imrecoxib cytochrome P450 metabolism liver microsomes rats |
| ISSN号 | 1671-4083 |
| 其他题名 | Formation of 4′-carboxyl acid metabolite of imrecoxib by rat liver microsomes |
| 英文摘要 | 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. |
| 语种 | 英语 |
| CSCD记录号 | CSCD:2462105 |
| 源URL | [http://ir.imr.ac.cn/handle/321006/158138]  |
| 专题 | 金属研究所_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. |
入库方式： OAI收割
来源：金属研究所
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