Abstract

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 thet_max was achieved at 9 h postdose. After t_max, levels of both radioactivity and rofecoxib decreased in a parallel, exponential fashion (effectivet_1/2 ≈ 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.