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, α-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 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 1A, 2C, 2D, and 2E, seem unlikely to participate in this metabolic pathway.
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Project supported by the National High Technology Research and Development Program of China (No 2003AA2Z347C)
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Xu, Hy., Zhang, P., Gong, As. et al. Formation of 4′-carboxyl acid metabolite of imrecoxib by rat liver microsomes. Acta Pharmacol Sin 27, 506–512 (2006). https://doi.org/10.1111/j.1745-7254.2006.00312.x
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DOI: https://doi.org/10.1111/j.1745-7254.2006.00312.x
