Role of human liver cytochrome P4503A in the metabolism of etoricoxib, a novel cyclooxygenase-2 selective inhibitor

Etoricoxib, a potent and selective cyclooxygenase-2 inhibitor, was shown to be metabolized via 6'-methylhydroxylation (M2 formation) when incubated wi th NADPH-fortified human liver microsomes. In agreement with in vivo data, 1'-N'-oxidation was a relatively minor pathway. Over the etoricoxib concent ration range studied (1-1300 muM), the rate of hydroxylation conformed to s aturable Michaelis-Menten kinetics (apparent K-m = 186 +/- 84.3 muM; V-max = 0.76 +/- 0.45 nmol/min/mg of protein; mean +/- S.D., n = 3 livers) and yi elded a V-max/K-m ratio of 2.4 to 7.3 mul/min/mg. This in vitro V-max/K-m r atio was scaled, with respect to yield of liver microsomal protein and live r weight, to obtain estimates of M2 formation clearance (3.1-9.7 ml/min/kg of b.wt.) that agreed favorably with in vivo results (8.3 ml/min/kg of b.wt .) following i.v. administration of [C-14]etoricoxib to healthy male subjec ts. Cytochrome P450 (P450) reaction phenotyping studies-using P450 form sel ective chemical inhibitors, immunoinhibitory antibodies, recombinant P450s, and correlation analysis with microsomes prepared from a bank of human liv ers-revealed that the 6'-methyl hydroxylation of etoricoxib was catalyzed l argely (60%) by member(s) of the CYP3A subfamily. By comparison, CYP2C9 (si milar to 10%), CYP2D6 (similar to 10%), CYP1A2 (similar to 10%), and possib ly CYP2C19 played an ancillary role. Moreover, etoricoxib (0.1-100 muM) was found to be a relatively weak inhibitor (IC50 > 100 muM) of multiple P450s (CYP1A2, CYP2D6, CYP3A, CYP2E1, CYP2C9, and CYP2C19) in human liver micros omes.