RT Journal Article SR Electronic T1 PHARMACOKINETICS AND METABOLISM OF LUMIRACOXIB IN HEALTHY MALE SUBJECTS JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 566 OP 571 DO 10.1124/dmd.32.5.566 VO 32 IS 5 A1 James B. Mangold A1 Helen Gu A1 Lolita C. Rodriguez A1 Johanne Bonner A1 Janet Dickson A1 Christiane Rordorf YR 2004 UL http://dmd.aspetjournals.org/content/32/5/566.abstract AB Lumiracoxib (Prexige; 2-[(2-fluoro-6-chlorophenyl)amino]-5-methyl-benzeneacetic acid) is a novel, chemically distinct cyclooxygenase-2 selective inhibitor, which has been developed for the treatment of osteoarthritis, rheumatoid arthritis, and acute pain. The absorption, metabolism, disposition, and mass balance of [14C]lumiracoxib were investigated in four healthy male subjects after a single 400-mg oral dose. Serial blood and complete urine and feces were collected for 168 h postdose. Lumiracoxib was rapidly absorbed, achieving mean plasma concentrations >1 μg/ml within 1 h of dosing. Unchanged drug in plasma accounted for 81 to 91% of radioactivity up to 2.5 h postdose, suggesting a modest first-pass effect; unchanged drug was the major circulating component in plasma, accounting for ∼43% of the AUC0 to 24h. The terminal half-life of lumiracoxib in plasma was 6.5 h. Major plasma metabolites were the 5-carboxy, 4′-hydroxy, and 4′-hydroxy-5-carboxy derivatives. Excretion involved both renal (54.1%) and fecal (42.7%) routes, and dose recovery was almost complete (96.8%). Lumiracoxib was extensively metabolized before excretion, with little unchanged drug in urine (3.3% of dose) or feces (2.0% of dose). The major metabolic pathways of lumiracoxib were oxidation of the 5-methyl group and hydroxylation of the dihaloaromatic ring. Glucuronic acid conjugates of lumiracoxib metabolites (and to a minor extent lumiracoxib itself) were identified, although there was no evidence of cysteine, mercapturic acid, or glutathione conjugates. In summary, orally administered lumiracoxib is rapidly absorbed and undergoes extensive metabolism before excretion via urine and feces, with no evidence of formation of potentially reactive metabolites. The American Society for Pharmacology and Experimental Therapeutics