Studies on the Metabolism of 4'-Chloro-5-methoxy-3-biphenylylacetic Acid (DKA-9) in Rat and the Anti-inflammatory Activity of DKA-9 and Its Metabolites

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Abstract
The metabolic fate of 4''-chloro-5-methoxy-3-biphenylylacetic acid (DKA-9), a newly developed anti-inflammatory drug, was examined in rats after i.v. administration of 14C-DKA-9. DKA-9 was metabolized mainly through 2 major pathways, glucuronide formation and demethylation followed by sulfate formation. The metabolites in urine and bile were fractionated by the combination of solvent extraction and preparative TLC. Five metabolites were detected and the structure of these metabolites was investigated from spectral and elemental analysis data. The major metabolites were identified as potassium 4''-chloro-5-hydroxy-3-biphenylylacetic acid O-sulfate (72.4% of the dose in 24 h) in urine, 1-(4''-chloro-5-methoxy-3-biphenylylacetoxy)glucuronic acid (28.0% of the dose in 6 h) in bile, and DKA-9 (5.2% of the dose in 48 h) in feces, and the minor metabolites were also identified as 4''-chloro-5-hydroxy-3-biphenylylacetic acid, 2-(4''-chloro-5-methoxy-3-biphenylyl)-2-hydroxyacetic acid and (4''-chloro-5-methoxy-3-biphenylylacetyl)glycine. The anti-inflammatory action of DKA-9 and its metabolites were also investigated by the inhibition of carrageenan-induced edema. There was no active metabolite and, therefore, the anti-inflammatory effect of DKA-9 in the rat seemed to be due to the action of DKA-9 itself.