SELECTIVE CYCLOOXYGENASE-2 INHIBITOR , IN HEALTHY MALE VOLUNTEERS

[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 ( 75%) present in plasma following both i.v. and p.o. doses. The oral dose, administered as a solution in polyethylene glycol400, was well absorbed (absolute bioavailability of 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 (>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. Nonsteroidal antiinflammatory drugs are widely used for the treatment of pain, inflammation, and fever. Their mechanism of action involves the inhibition of COX, a hemeprotein that exists in two forms (COX-1 and COX-2) and converts arachidonic acid to proinflammatory prostaglandins and their subsequent metabolic products (Donnelly and Hawkey, 1997; Jouzeau et al., 1997; Lane, 1997; Lipsky and Isakson, 1997). Because the products of COX-1 are cytoprotective, selective inhibition of COX-2 can reduce inflammation with less of the gastrointestinal side effects characteristic of nonselective nonsteroidal antiinflammatory drugs. Therefore, much attention has been focused on the design of potent and selective COX-2 inhibitors like etoricoxib (5-chloro-6 -methyl-3-[4-(methylsulfonyl)phenyl]-2,3 -bipyridine; ARCOXIA ), which has been developed for acute and chronic analgesia, the treatment of the signs and symptoms of osteoarthritis, rheumatoid arthritis, dysmenorrhea, and gouty arthritis (Chauret et al., 2001; Ouellet et al., 2001; Riendeau et al., 2001; Sorbera et al., 2001). Etoricoxib pharmacokinetics are linear at clinically relevant doses and the pharmacokinetic half-life, and pharmacological response, supports oral once-a-day dosing (Agrawal et al., 2001, 2002). In addition, the results of in vitro metabolism studies have indicated that etoricoxib is metabolized via 6 -methyl hydroxylation and 1 -N-oxidation (Fig. 1). These metabolites, which do not inhibit COX-1 and do not contribute significantly to the inhibition of COX-2, are formed by P450s (Chauret et al., 2001; Kassahun et al., 2001). Although the in vitro metabolism of etoricoxib has been described, its absorption, disposition, and metabolism in man have yet to be reported. Therefore, the study presented here describes the absorption and disposition of [C]etoricoxib in human subjects. The specific objectives of this study were 1) to investigate the routes of elimination of etoricoxib in healthy subjects following single oral and i.v. doses of [C]etoricoxib, 2) to quantitate concentrations of total radioactivity and etoricoxib in plasma after single oral and i.v. doses of radiolabeled etoricoxib, 3) to examine the metabolism of etoricoxib in humans, 4) to demonstrate mass balance for [C]etoricoxib in humans, and 5) to estimate the absolute bioavailability of etoricoxib administered as an oral solution. Materials and Methods Chemicals. [C]Etoricoxib ( 99% radiochemical purity) was synthesized by the Labeled Compound Synthesis Group (Merck Research Laboratories, Rahway, NJ). The Carbon-14 label was incorporated at the methyl group of the methane sulfonyl phenyl moiety (Fig. 1). Standards of the 1 -N -oxide, 6 hydroxymethyl, 6 -hydroxymethyl-1 -N -oxide, and 6 -carboxy metabolites of 1 Abbreviations used are: COX, cyclooxygenase; etoricoxib (ARCOXIA), 5-chloro-6 -methyl-3-[4-(methylsulfonyl)phenyl]-2,3 -bipyridine; P450, cytochrome P450; HPLC, high performance liquid chromatography; PEG, polyethylene glycol; LC-MS/MS, liquid chromatography tandem mass spectrometry; ESI, electrospray ionization; solvent A, aqueous 0.1% formic acid; solvent B, 0.1% formic acid in acetonitrile; AUC, area under the plasma concentrations versus time curve; Cl, clearance; Vdss, steady-state volume of distribution; Tmax, time of occurrence of maximal concentration in plasma; AUMC, area under the first moment curve; MRT, mean residence time; , infusion time; ANOVA, analysis of variance; GMR, geometric mean ratio; CI, confidence interval. 2 ARCOXIA is a registered trademark of Merck & Co., Inc. Address correspondence to: A. David Rodrigues, Ph.D., Department of Drug Metabolism, WP75A-203, Merck Research Laboratories, West Point PA 19486. E-mail: david_rodrigues@merck.com 0090-9556/03/31002-224–232$7.00 DRUG METABOLISM AND DISPOSITION Vol. 31, No. 02 Copyright © 2003 by The American Society for Pharmacology and Experimental Therapeutics 876/1041048 DMD 31:224–232, 2003 Printed in U.S.A. 224 at A PE T Jornals on Jne 3, 2017 dm d.aspurnals. org D ow nladed from