Studies on the Metabolism of 4'-Chloro-5-methoxy-3-biphenylylacetic Acid (DKA-9) in Human and Various Animal Species

The metabolic fate and species difference of 4'-chloro-5-methoxy-3-biphenylylacetic acid (DKA-9), a newly developed anti-inflammatory drug, were studied in human and various animal species (mouse, guinea pig, rabbit, beagle dog, rhesus monkey) by intravenous, intraperitoneal, or oral administration of DKA-9. It was found that men, mice, guinea pigs, and rabbits excreted DKA-9 and its metabolites mainly in urine and the dog mainly in feces (78.8, 75.3, 77.3, 88.7 and 79.1% of the dose, respectively) and there was prolongation of urinary excretion in guinea pigs and rabbits. The detection and fractionation of metabolites in urine and bile were performed by the combination of solvent extraction, enzymic and chemical hydrolysis, and thin-layer chromatography, and nine metabolites were detected. The structures of metabolites fractionated were investigated from spectral analysis data and identified to be 4'-chloro-5-hydroxy-3-biphenylylacetic acid, 5-carboxymethyl-4'-chloro-3-biphenylyl hydrogen sulfate (mainly in mice, guinea pigs, and monkeys), 2-(4'-chloro-5-methoxy-3-biphenylyl)-2-hydroxyacetic acid (mainly in dogs), 4'-chloro-5-methoxy-3-biphenylylacetyl β-D-glucopyranosiduronic acid (mainly in men), 5-carboxymethyl-4'-chloro-3-biphenylyl β-D-glucopyranosiduronic acid (mainly in rabbits), and 4'-chloro-5-hydroxy-3-biphenylylacetyl-β-D-glucopyranosiduronic acid. A metabolite which may be hydroxylated at the 4- or 6-position of DKA-9, its sulfate, and its glucuronide were also detected in mouse and dog urine but not identified yet. Though there are considerable species difference of the metabolic pattern in urine, the main metabolite in the bile was 4'-chloro-5-methoxy-3-biphenylylacetyl β-D-glucopyranosiduronic acid, common to all species.