PT  - JOURNAL ARTICLE
AU  - Rita A. Halpin
AU  - Arturo G. Porras
AU  - Leslie A. Geer
AU  - Margaret R. Davis
AU  - Donghui Cui
AU  - George A. Doss
AU  - Eric Woolf
AU  - Donald Musson
AU  - Catherine Matthews
AU  - Ralph Mazenko
AU  - Jules I. Schwartz
AU  - Kenneth C. Lasseter
AU  - Kamlesh P. Vyas
AU  - Thomas A. Baillie
TI  - The Disposition and Metabolism of Rofecoxib, a Potent and Selective Cyclooxygenase-2 Inhibitor, in Human Subjects
AID  - 10.1124/dmd.30.6.684
DP  - 2002 Jun 01
TA  - Drug Metabolism and Disposition
PG  - 684--693
VI  - 30
IP  - 6
4099  - http://dmd.aspetjournals.org/content/30/6/684.short
4100  - http://dmd.aspetjournals.org/content/30/6/684.full
SO  - Drug Metab Dispos2002 Jun 01; 30
AB  - The disposition and metabolism of rofecoxib, a selective cyclooxygenase-2 inhibitor, were examined in healthy human subjects and in cholecystectomy patients. After oral administration of [14C]rofecoxib (125 mg, 100 μCi) to healthy subjects, the mean concentrations of total radioactivity and rofecoxib in plasma as a function of time indicated that thetmax was achieved at 9 h postdose. After tmax, levels of both radioactivity and rofecoxib decreased in a parallel, exponential fashion (effectivet1/2 ≈ 17 h). A similar result was obtained after oral administration of [14C]rofecoxib (142 mg, 100 μCi) to cholecystectomy patients equipped with an L-tube. In healthy subjects, radioactivity was recovered predominantly from the urine (71.5% of dose), with a small amount excreted in feces (14.2%). In patients with an L-tube, half the radioactive dose was recovered in feces, with a lesser amount excreted in urine (28.8%) and a negligible fraction in bile (1.8%). Rofecoxib underwent extensive metabolism in humans, and very little parent drug was recovered unchanged in urine (<1%). Products resulting from both oxidative and reductive pathways were identified by a combination of 1H NMR and liquid chromatography-tandem mass spectrometry analyses, and included rofecoxib-3′,4′-trans-dihydrodiol, 4′-hydroxyrofecoxib-O-β-d-glucuronide, diastereomeric 5-hydroxyrofecoxib-O-β-d-glucuronide conjugates, 5-hydroxyrofecoxib, rofecoxib-erythro-3,4-dihydrohydroxy acid, and rofecoxib-threo-3,4-dihydrohydroxy acid. Interconversion of rofecoxib and 5-hydroxyrofecoxib appeared not to be a quantitatively important pathway of rofecoxib disposition in human subjects, in contrast to previous findings in rats. The American Society for Pharmacology and Experimental Therapeutics