title: Role of human liver cytochrome P4503A in the metabolism of etoricoxib, a novel cyclooxygenase-2 selective inhibitor.
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 microM), the rate of hydroxylation conformed to saturable Michaelis-Menten kinetics (apparent K(m) = 186 +/- 84.3 microM; 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 microl/min/mg. This in vitro V(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 [(14)C]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 (approximately 60%) by member(s) of the CYP3A subfamily. By comparison, CYP2C9 (approximately 10%), CYP2D6 (approximately 10%), CYP1A2 (approximately 10%), and possibly CYP2C19 played an ancillary role. Moreover, etoricoxib (0.1-100 microM) was found to be a relatively weak inhibitor (IC(50) > 100 microM) of multiple P450s (CYP1A2, CYP2D6, CYP3A, CYP2E1, CYP2C9, and CYP2C19) in human liver microsomes.
authors.affiliation: Department of Drug Metabolism, Merck Research Laboratories, West Point, Pennsylvania 19486-0004, USA. kelem_kassahun@merck.com.
authors.forename: K
authors.initials: K
authors.lastname: Kassahun
authors.forename: I S
authors.initials: IS
authors.lastname: McIntosh
authors.forename: M
authors.initials: M
authors.lastname: Shou
authors.forename: D J
authors.initials: DJ
authors.lastname: Walsh
authors.forename: C
authors.initials: C
authors.lastname: Rodeheffer
authors.forename: D E
authors.initials: DE
authors.lastname: Slaughter
authors.forename: L A
authors.initials: LA
authors.lastname: Geer
authors.forename: R A
authors.initials: RA
authors.lastname: Halpin
authors.forename: N
authors.initials: N
authors.lastname: Agrawal
authors.forename: A D
authors.initials: AD
authors.lastname: Rodrigues
mesh_terms: D000818:Animals; D002460:Cell Line; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000493:pharmacokinetics*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D018076:DNA, Complementary; D000077613:Etoricoxib; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins; D008862:Microsomes, Liver / Q000201:enzymology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects; D011725:Pyridines / Q000493:pharmacokinetics*; D013450:Sulfones / Q000493:pharmacokinetics*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D018076:DNA, Complementary; D007527:Isoenzymes; D008565:Membrane Proteins; D011725:Pyridines; D013450:Sulfones; D003577:Cytochrome P-450 Enzyme System; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D000077613:Etoricoxib