Metabolism of 6-Chloro-5-cyclohexylindane-1-carboxylic Acid (TAI-284), a New Non-steroidal Anti-inflammatory Agent. I. Absorption, Distribution and Excretion in Rats

Abstract

1. In rats, a new non-steroidal anti-inflammatory agent, 6-chloro-5-cyclohexylindane-1-carboxylic acid (TAI-284), labelled with ³H, was almost quantitatively absorbed, mainly from the small intestine. Gastric absorption was also demonstrated.

2. The plasma concn. of the orally administered drug reached a peak at 2 h with a half-life of about 7·5 h. The concn. after intravenous injection decreased biphasically with t_0·5 values of 20 and 80 min. About half of the plasma radioactivity was the intact drug, of which more than 90% was bound to plasma protein. Plasma metabolites, detected by t.l.c., were the 4′-oxocyclohexyl derivative (I), a mixture of cis-4′- and cis-3′-hydroxycyclohexyl derivatives (IIa and IIb), trans-4′-hydroxycyclohexyl derivative (III) and cis-3′-hydroxycyclohexyl derivative (IV), together with small amounts of unidentified polar metabolites (V and VI). Metabolites IIb and IV are diastereoisomers.

3. TAI-284, administered orally or intravenously, was widely distributed, with high concn. in stomach, duodenum, liver, small intestine, adrenal and kidney, but far less in brain. The concns. in most tissues were lower than the blood level. Distribution of radioactivity in inflamed tissues was also demonstrated.

4. Oral TAI-284 was completely eliminated from the body within 72 h, with 46·3 and 50·2% of the dose being excreted in urine and faeces, respectively. Some portion of the metabolites was excreted in bile to enter into entero-hepatic cycling.

5. TAI-284 accounted for only a few per cent of the radioactivity in excreta. The major urinary and faecal metabolites were V, VI and III, while most of the biliary radioactivity was derived from metabolite VI.

6. After intravenous injection of [³H]TAI-284 to a pregnant rat radioactivity was transferred to foetuses.