Metabolism of 6-Chloro-5-cyclohexylindane-1-carboxylic Acid (TAI-284), a New Non-steroidal Anti-inflammatory Agent. II. Isolation and Identification of Metabolites in the Perfusate of the Isolated Liver Perfusion in Rats

Abstract

1. Biotransformation of 6-chloro-5-cyclohexylindane-1-carboxylic acid labelled with tritium and deuterium was studied in isolated perfused rat liver. Five metabolites were isolated by column and thin-layer chromatography. 2. The metabolites and their methyl esters were characterized by mass and proton magnetic resonance spectrometry with aid of a shift reagent, tris(dipivalomethanato)europium. The following metabolites were identified : 6-chloro-5-(4′-oxocyclohexyl)indane-1-carboxylic acid(metabolite I),6-chloro-5-(cis-4′-hydroxycyclohexyl)indane-1-carboxylic acid (metabolite IIa), 6-chloro-5-(trans-4′-hydroxycyclohexyl)indane-1-carboxylic acid (metabolite III), 6-chloro-5-(cis-3′-hydroxycyclohexyl)indane-1-carboxylic acid (metabolite IV or IIb). Metabolites IV and IIb are diastereoisomers. 3. The compound was metabolized primarily by hydroxylation producing metabolites IIa (cis-4′-ol), IIb (cis-3′-ol), III (trans-4′-ol) and IV (cis-3′-ol). Metabolites IIa and III seemed to be further metabolized to I (4′-oxo).