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 [ 14 C]rofecoxib (125 mg, 100 Ci) to healthy subjects, the mean concentrations of total radioactivity and rofecoxib in plasma as a function of time indicated that the t max was achieved at 9 h postdose. After t max , levels of both radioactivity and rofecoxib decreased in a parallel, exponential fashion (effective t (Prasit et al., 1999), an inducible isoform of cyclooxygenase that plays a key role in inflammatory processes. Rofecoxib has been approved for the treatment of arthritis and pain, and was developed on the premise that selective inhibition of COX-2 would result in decreased inflammation without the adverse gastrointestinal effects associated with inhibition of COX-1 (Vane and Botting, 1996; Donnelly and Hawkey, 1997; Jouzeau et al., 1997). This hypothesis has been supported by the results of recent clinical trials, including the VIGOR study, in which rheumatoid arthritis patients treated with rofecoxib displayed significantly fewer clinically important gastrointestinal events than patients treated with naproxen, a nonselective COX inhibitor (Bombardier et al., 2000).1Disposition and metabolism of rofecoxib in rats and dogs were reported recently (Halpin et al., 2000); metabolites identified in both species included 5-hydroxyrofecoxib, 5-hydroxyrofecoxib-O-␤-Dglucuronide, and trans-3,4-dihydro-rofecoxib, while additional metabolites identified in rat only were cis-3,4-dihydro-rofecoxib, rofecoxib-3Ј,4Ј-dihydrodiol, and 4Ј-hydroxyrofecoxib sulfate. Of note, following oral administration of rofecoxib to intact rats, was the appearance of a second C max which was not observed in bile duct-cannulated rats. This phenomenon was found to be due to a novel form of enterohepatic recycling, which involved reversible metabolism of rofecoxib to 5-hydroxyrofecoxib (Baillie et al., 2001).The studies presented here describe the disposition and metabolism of rofecoxib in human subjects. The specific objectives of these studies were: 1) to examine the absorption and excretion of [ 14 C]rofecoxib in healthy adult volunteers and to compare the results with those obtained from animals, 2) to identify the urinary metabolites of rofecoxib in humans, 3) to examine the extent of conversion of 5-hydroxyrofecoxib to rofecoxib following oral administration of 5-hydroxyrofecoxib to healthy subjects, and 4) to investigate the possible involvement of biliary elimination in the excretion of rofecoxib and its metabolites in humans.

The single- and multiple-dose pharmacokinetics of etoricoxib, a selective inhibitor of cyclooxygenase-2, were examined in two clinical studies. Single-dose pharmacokinetics--including dose proportionality, absolute bioavailability of the highest dose-strength (120-mg) tablet, and the effect of a high-fat meal on the bioavailability of that tablet--were investigated in a two-part, open, balanced crossover study in two panels of healthy subjects (12 per panel). Steady-state pharmacokinetics were investigated in an open-label study in which 24 healthy subjects were administered 120-mg single and multiple (once daily for 10 days) oral doses of etoricoxib tablets. The pharmacokinetics of etoricoxib were found to be consistent with linearity through doses at least twofold greater than the highest anticipated clinical dose of 120 mg. Etoricoxib administered as a tablet was rapidly and completely absorbed and available; the absolute bioavailability was estimated to be 100%. A high-fat meal decreased the rate of absorption without affecting the extent of absorption of etoricoxib; therefore, etoricoxib can be dosed irrespective of food. Steady-state pharmacokinetics of etoricoxib, achieved following 7 days of once-daily dosing, were found to be reasonably predicted from single doses. The accumulation ratio averaged 2.1, and the corresponding accumulation t1/2 averaged 22 hours, supporting once-daily dosing. Etoricoxib was generally well tolerated.

ABSTRACT:[ 14 C]Etoricoxib (100 Ci/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 (ϳ75%) 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 ϳ83%). 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 (>65% of the total radioactivity). 6-Hydroxymethyl-etoricoxib and etoricoxib-1-N-oxide, as well as the O-␤-D-glucuronide conjugate and the 1-N-oxide derivative of 6-hydroxymethyl-etoricoxib, were present in the excreta also (individually, <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.

To assess dose proportionality of etoricoxib across the anticipated clinical dose range, a single panel of 12 healthy subjects was administered single oral doses of etoricoxib of 5, 10, 20, 40, and 120 mg in an open, two-part, five-period crossover study. Plasma samples were collected aftereach dose and analyzed for etoricoxib concentrations. The pharmacokinetics of etoricoxib appear to be linear over the entire dose range examined, from 5 to 120 mg. Etoricoxib was found to be well tolerated across the 5 to 120 mg dose range.

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