RT Journal Article
SR Electronic
T1 The Disposition and Metabolism of Rofecoxib, a Potent and Selective Cyclooxygenase-2 Inhibitor, in Human Subjects
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 684
OP 693
DO 10.1124/dmd.30.6.684
VO 30
IS 6
A1 Halpin, Rita A.
A1 Porras, Arturo G.
A1 Geer, Leslie A.
A1 Davis, Margaret R.
A1 Cui, Donghui
A1 Doss, George A.
A1 Woolf, Eric
A1 Musson, Donald
A1 Matthews, Catherine
A1 Mazenko, Ralph
A1 Schwartz, Jules I.
A1 Lasseter, Kenneth C.
A1 Vyas, Kamlesh P.
A1 Baillie, Thomas A.
YR 2002
UL http://dmd.aspetjournals.org/content/30/6/684.abstract
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