In vitro metabolism considerations, including activity testing of metabolites, in the discovery and selection of the COX-2 inhibitor etoricoxib (MK-0663).
Characterization of the metabolites of the COX-2 inhibitor etoricoxib (MK-0663 and L-791,456) produced in vitro indicate formation of an N-oxide pyridine and hydroxymethyl pyridine that can further be glucuronidated or oxidized to an acid. Significant turnover is observed in human hepatocytes. Several CYPs are involved in the oxidative biotranformations and, from in vitro studies, etoricoxib is not a potent CYP3A4 inducer or inhibitor. Based on an in vitro whole blood assay, none of the metabolites of etoricoxib inhibits COX-1 or contributes significantly to the inhibition of COX-2.
Chauret
N
N
Merck Frosst Centre for Therapeutic Research, Pointe-Claire-Dorval, Quebec, Canada. nathalie_chauret@merck.com
Yergey
J A
JA
Brideau
C
C
Friesen
R W
RW
Mancini
J
J
Riendeau
D
D
Silva
J
J
Styhler
A
A
Trimble
L A
LA
Nicoll-Griffith
D A
DA
D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000378:metabolism / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D000077613:Etoricoxib; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000097:blood; D008565:Membrane Proteins; D008861:Microsomes / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D010084:Oxidation-Reduction; D011451:Prostaglandin-Endoperoxide Synthases / Q000097:blood; D011725:Pyridines / Q000378:metabolism* / Q000494:pharmacology*; D013450:Sulfones / Q000378:metabolism* / Q000494:pharmacology*
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D011725:Pyridines; D013450:Sulfones; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D000077613:Etoricoxib