| Formation of 4 '-carboxyl acid metabolite of imrecoxib by rat liver microsomes | |
| Alternative Title | Formation of 4′-carboxyl acid metabolite of imrecoxib by rat liver microsomes |
| Xu HY1; Zhang P1; Gong AS1; Sun YM1; Chu FM1; Guo ZR1; Zhong DF1 | |
| 2006 | |
| Source Publication | ACTA PHARMACOLOGICA SINICA
 |
| ISSN | 1671-4083 |
| Volume | 27Issue:4Pages:506-512 |
| Abstract | 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. |
| Other Abstract | 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. |
| Keyword | PRIMARY CULTURES CYCLOOXYGENASE-2 HEPATOCYTES INDUCTION imrecoxib cytochrome P450 metabolism liver microsomes rats |
| Indexed By | CSCD |
| Language | 英语 |
| CSCD ID | CSCD:2462105 |
| Citation statistics | |
| Document Type | 期刊论文 |
| Identifier | http://ir.imr.ac.cn/handle/321006/158139 |
| Collection | 中国科学院金属研究所 |
| Affiliation | 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 |
| Recommended Citation 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. |
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