Metabolism of 6-Chloro-5-cyclohexylindan-1-carboxylic Acid (TAI-284), a New Non-steroidal Anti-inflammatory Agent, in Relation to Ulcerogenic Activity

Abstract

6-Chloro-5-cyclohexylindan-1-carboxylic acid (TAI-284) and its cis-3′-hydroxy metabolite, IIb, produced focal ulcers on the mesenteric side of the distal small intestine of rats. The ulcerogenic activity of TAI-284 was more pronounced in male than in female rats. Pre-treatment of male rats with either phenobarbital or 2-diethylaminoethyl 2,2-diphenylvalerate hydrochloride (SKF 525-A) decreased the development of TAI-284-induced intestinal ulceration.

The comparative resistance of males pre-treated with phenobarbital or SKF 525-A, and of females, to ulceration was related to the plasma level of the ulcerogenic metabolite IIb, but not to that of the parent compound. The rate of formation of metabolite IIb by liver 11 000 g supernatant fractions was slower in males pre-treated with SKF 525-A, and in females, than in non-treated males.

The major biliary metabolite(s), VI, were glucuronic acid esters of TAI-284 and its oxo or hydroxy metabolites. The rate of formation and subsequent biliary excretion of metabolite IIb was much slower in mice and guinea-pigs than in rats; the former two species being much less susceptible to the TAI-284-induced intestinal ulceration than rats. About 70% or more of this metabolite was present as glucuronide in rat and mouse bile, but no significant amount of glucuronide was detected in guinea-pig bile.

These findings strongly suggest that metabolite IIb plays a more important role than the parent compound in development of intestinal ulcer in rats, and also that the species variation in ulceration was due, at least partly, to formation of this metabolite in the body.