Absorption, metabolism, and excretion of etoricoxib, a potent and selective cyclooxygenase-2 inhibitor, in healthy male volunteers.
[(14)C]Etoricoxib (100 microCi/dose) was administered to six healthy male subjects (i.v., 25 mg; p.o., 100 mg). Following the i.v. dose, the plasma clearance was 57 ml/min, and the harmonic mean half-life was 24.8 h. Etoricoxib accounted for the majority of the radioactivity (approximately 75%) present in plasma following both i.v. and p.o. doses. The oral dose, administered as a solution in polyethylene glycol-400, was well absorbed (absolute bioavailability of approximately 83%). Total recovery of radioactivity in the excreta was 90% (i.v.) and 80% (p.o.), with 70% (i.v.) and 60% (p.o.) excreted in urine and 20% in feces after either route of administration. Radiochromatographic analysis of the excreta revealed that etoricoxib was metabolized extensively, and only a minor fraction of the dose (<1%) was excreted unchanged. Radiochromatograms of urine and feces showed that the 6'-carboxylic acid derivative of etoricoxib was the major metabolite observed (> or =65% of the total radioactivity). 6'-Hydroxymethyl-etoricoxib and etoricoxib-1'-N-oxide, as well as the O-beta-D-glucuronide conjugate and the 1'-N-oxide derivative of 6'-hydroxymethyl-etoricoxib, were present in the excreta also (individually, < or =10% of the total radioactivity). In healthy male subjects, therefore, etoricoxib is well absorbed, is metabolized extensively via oxidation (6'-methyl oxidation >1'-N-oxidation), and the metabolites are excreted largely in the urine.
Rodrigues
A David
AD
Department of Drug Metabolism, WP75A-203, Merck Research Laboratories, West Point, PA 19486, USA. david_rodrigues@merck.com
Halpin
Rita A
RA
Geer
Leslie A
LA
Cui
Donghui
D
Woolf
Eric J
EJ
Matthews
Catherine Z
CZ
Gottesdiener
Keith M
KM
Larson
Patrick J
PJ
Lasseter
Kenneth C
KC
Agrawal
Nancy G B
NG
D000704:Analysis of Variance; D019540:Area Under Curve; D018592:Cross-Over Studies; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism* / Q000652:urine; D000077613:Etoricoxib; D005243:Feces / Q000201:enzymology; D006801:Humans; D007408:Intestinal Absorption / Q000502:physiology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011725:Pyridines / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism* / Q000652:urine; D013450:Sulfones / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism* / Q000652:urine
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D011725:Pyridines; D013450:Sulfones; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D000077613:Etoricoxib