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

Article Details

Citation

Kassahun K, McIntosh IS, Shou M, Walsh DJ, Rodeheffer C, Slaughter DE, Geer LA, Halpin RA, Agrawal N, Rodrigues AD

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

Drug Metab Dispos. 2001 Jun;29(6):813-20.

PubMed ID
11353749 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
EtoricoxibCytochrome P450 1A2ProteinHumans
Unknown
Substrate
Details
EtoricoxibCytochrome P450 2C19ProteinHumans
Unknown
Inhibitor
Details
EtoricoxibCytochrome P450 2C9ProteinHumans
Unknown
Substrate
Inhibitor
Details
EtoricoxibCytochrome P450 2E1ProteinHumans
Unknown
Inhibitor
Details