Abstract

Etoricoxib, a potent and selective cyclooxygenase-2 inhibitor, was shown to be metabolized via 6′-methylhydroxylation (M2 formation) when incubated with NADPH-fortified human liver microsomes. In agreement with in vivo data, 1′-N′-oxidation was a relatively minor pathway. Over the etoricoxib concentration range studied (1–1300 μM), the rate of hydroxylation conformed to saturable Michaelis-Menten kinetics (apparent K _m = 186 ± 84.3 μM; V _max = 0.76 ± 0.45 nmol/min/mg of protein; mean ± S.D., n = 3 livers) and yielded a V _max/K_m ratio of 2.4 to 7.3 μl/min/mg. This in vitroV _max/K _m ratio was scaled, with respect to yield of liver microsomal protein and liver 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 [¹⁴C]etoricoxib to healthy male subjects. Cytochrome P450 (P450) reaction phenotyping studies—using P450 form selective chemical inhibitors, immunoinhibitory antibodies, recombinant P450s, and correlation analysis with microsomes prepared from a bank of human livers—revealed that the 6′-methyl hydroxylation of etoricoxib was catalyzed largely (∼60%) by member(s) of the CYP3A subfamily. By comparison, CYP2C9 (∼10%), CYP2D6 (∼10%), CYP1A2 (∼10%), and possibly CYP2C19 played an ancillary role. Moreover, etoricoxib (0.1–100 μM) was found to be a relatively weak inhibitor (IC₅₀ > 100 μM) of multiple P450s (CYP1A2, CYP2D6, CYP3A, CYP2E1, CYP2C9, and CYP2C19) in human liver microsomes.