METABOLIC DISPOSITION OF ISOXICAM IN MAN, MONKEY, DOG, AND RAT

Abstract

Isoxicam, a new nonsteroidal antiinflammatory agent, was radiolabeled with 14C at the 3-position of the benzothiazine nucleus. It was well absorbed following peroral administration to man, rhesus monkey, dog and rat, reaching peak plasma concentrations in 4-8 h. Over 90% of the plasma radioactivity was due to unchanged drug. Plasma elimination half-lives were 22-45 h in man, 49-53 h in dogs and 20-35 h in rats and monkeys. Isoxicam was distributed to most tissues in rats, but the tissue-plasma ratio did not exceed unity, indicating a small volume of distribution. It was extensively metabolized, with only a few percent of the dose appearing as unchanged drug in the urine. The principal urinary metabolite in man was formed by hydroxylation of the methyl group on the isoxozole ring, and it accounted for 30-35% of an isoxicam dose. In the rat, oxoacetic acid, the major urinary metabolite, was formed by opening of the benzothiazine ring followed by hydrolytic cleavage of the C-3 to N-2 bond. In addition to the hydroxymethyl and oxoacetic acid, 2 unknown metabolites, accounting for only a small percentage of dose, were detected in the urine of all 4 species. Urinary excretion of 14 C activity accounted for about 60% of a dose in man and rats, 31% in monkeys and 17% in dogs. There is evidently only a quantitative rather than a qualitative species difference in the metabolic disposition of isoxicam.