Metabolic Disposition of 6-Chloro-5-cyclohexyl-1-indancarboxylic Acid (TAI-284), a New Non-steroidal Anti-inflammatory Agent, in Rhesus Monkeys

Abstract

1. After oral administration of 6-chloro-5-cyclohexyl-1-indan[¹⁴C]carboxylic acid (TAI-284) to rhesus monkeys, the plasma concn. reached a plateau at 2 h, which persisted for 4 h and then declined with an approximate half-life of 24 h. More than 92% of the plasma radioactivity was derived from unchanged TAI-284. The plasma concn. of the ulcerogenic metabolite, 6-chloro-5-(cis-3'-hydroxycyclohexyl)-1-indancarboxylic acid (metabolite IIb), was much lower in monkeys than in rats.

2. In monkeys, elimination of the ingested radioactivity was complete in 96 h, the excretion being almost equally divided between urine and faeces. This excretory pattern was similar to that in rats. The major urinary metabolites in monkeys were TAI-284, 6-chloro-5-(trans-4'-hydroxycyclohexyl)-1-indancar-boxylic acid (metabolite III) and glucuronides of TAI-284 and its oxo or hydroxy derivatives (metabolite VI), whereas those in rats were dihydroxy derivatives of TAI-284 (metabolite V) and VI. Unchanged TAI-284 accounted for only a small part of the faecal radioactivity in monkeys and rats.

3. Both in monkeys and rats, some of the dose of radioactivity was excreted in bile to enter into entero-hepatic cycling. Biliary excretion of metabolite lib was markedly smaller in monkeys than in rats.

4. These metabolic findings are discussed in relation to the variation in the TAI-284-induced intestinal ulceration between monkeys and rats.