Formation of 4'-carboxyl acid metabolite of imrecoxib by rat liver microsomes.
OBJECTIVE
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 microsome. The formed metabolite was identified and quantified by LC/MS(n). 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.


CONCLUSIONS
These biotransformation studies of 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.
Laboratory of Drug Metabolism and Pharmacokinetics, Shenyang Pharmaceutical University, Shenyang 110016, China.
Hai-Yan
HY
Xu
Peng
P
Zhang
Ai-Shen
AS
Gong
Yu-Ming
YM
Sun
Feng-Ming
FM
Chu
Zong-Ru
ZR
Guo
Da-Fang
DF
Zhong
D000818:Animals; D001711:Biotransformation; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors; D003907:Dexamethasone / Q000494:pharmacology; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D011758:Pyrroles / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013440:Sulfides / Q000378:metabolism*
D065692:Cytochrome P-450 CYP3A Inhibitors; C488833:Imrecoxib; D011758:Pyrroles; D013440:Sulfides; D009249:NADP; D003907:Dexamethasone; D051544:Cytochrome P-450 CYP3A; D007654:Ketoconazole