Role of rat liver cytochrome P450 3A and 2D in metabolism of imrecoxib.
OBJECTIVE
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-carbonyl imrecoxib (M5). Over the imrecoxib concentration range studied (5-600 micromol/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 b-naphthoflavone-induced rats. In contrast, a-naphthoflavone, cimetidine, and methylpyrazole had no inhibitory effects on this metabolic pathway.


CONCLUSIONS
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 beta-naphthoflavone-induced rats.
Xu
Hai-yan
HY
Laboratory of Drug Metabolism and PharmacokineticsìShenyang Pharmaceutical University, Shenyang 110016, China.
Xie
Zhi-yong
ZY
Zhang
Peng
P
Sun
Jin
J
Chu
Feng-ming
FM
Guo
Zong-ru
ZR
Zhong
Da-fang
DF
D000818:Animals; D001711:Biotransformation; D052246:Cyclooxygenase 2 Inhibitors / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D011758:Pyrroles / Q000378:metabolism*; D011803:Quinine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013440:Sulfides / Q000378:metabolism*
D052246:Cyclooxygenase 2 Inhibitors; C488833:Imrecoxib; D011758:Pyrroles; D013440:Sulfides; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D011803:Quinine; D051544:Cytochrome P-450 CYP3A