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Role of rat liver cytochrome P450 3A and 2D in metabolism of imrecoxib
Alternative TitleRole of rat liver cytochrome P450 3A and 2D in metabolism of imrecoxib
Xu HY1; Xie ZY1; Zhang P1; Sun J1; Chu FM1; Guo ZR1; Zhong DF1
2006
Source PublicationACTA PHARMACOLOGICA SINICA
ISSN1671-4083
Volume27Issue:3Pages:372-380
AbstractAim: 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.
Other AbstractAim: 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.
KeywordNONSTEROIDAL ANTIINFLAMMATORY DRUGS COX-2 INHIBITORS IN-VITRO MICROSOMES CYCLOOXYGENASE-2 OSTEOARTHRITIS ISOENZYMES NSAIDS VIVO imrecoxib cytochrome P450 metabolism liver microsomes
Indexed ByCSCD
Language英语
CSCD IDCSCD:2621336
Citation statistics
Cited Times:1[CSCD]   [CSCD Record]
Document Type期刊论文
Identifierhttp://ir.imr.ac.cn/handle/321006/143851
Collection中国科学院金属研究所
Affiliation1.中国科学院金属研究所
2.中国科学院
3.Peking Union Med Coll
Recommended Citation
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.
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