Pharmacokinetics and metabolism of lumiracoxib in healthy male subjects.
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 microg/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 approximately 43% of the AUC(0 to 24 h). 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.
Mangold
James B
JB
Preclinical Safety-ADME, Novartis Pharmaceuticals Corporation, East Hanover, NJ 07936, USA. james.mangold@pharma.novartis.com
Gu
Helen
H
Rodriguez
Lolita C
LC
Bonner
Johanne
J
Dickson
Janet
J
Rordorf
Christiane
C
D000284:Administration, Oral; D000328:Adult; D004008:Diclofenac / Q000031:analogs & derivatives; D005243:Feces / Q000737:chemistry; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate / Q000502:physiology; D008875:Middle Aged; D009930:Organic Chemicals / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics* / Q000652:urine
D009930:Organic Chemicals; D004008:Diclofenac; C473384:lumiracoxib