RT Journal Article
SR Electronic
T1 Role of Human Liver Cytochrome P4503A in the Metabolism of Etoricoxib, a Novel Cyclooxygenase-2 Selective Inhibitor
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 813
OP 820
VO 29
IS 6
A1 Kelem Kassahun
A1 Ian S. McIntosh
A1 Magang Shou
A1 Deborah J. Walsh
A1 Carey Rodeheffer
A1 Donald E. Slaughter
A1 Leslie A. Geer
A1 Rita A. Halpin
A1 Nancy Agrawal
A1 A. David Rodrigues
YR 2001
UL http://dmd.aspetjournals.org/content/29/6/813.abstract
AB 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/Km 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. The American Society for Pharmacology and Experimental Therapeutics