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To characterize the pharmacokinetic properties of a new antirheumatic drug, KE-298, the metabolic fate of [14C]labeled KE-298 in rats was investigated, focussing especially on the identification of metabolites and its physiological properties. [14C]KE-298 was rapidly and almost completely absorbed after oral administration, and was well distributed throughout the body. In plasma, only a small amount of unchanged KE-298 was detected and the major component was an active metabolite, deacetyl-KE-298, which accounted for approximately 50% of the radioactivity in the plasma. Further evidence was obtained by 1H-NMR analysis that deacetyl-KE-298 existed as ketone-thiol and thiohemiacetal forms in a tautomeric equilibrium. As the second main metabolite in plasma, S-methyl-KE-298, a methyl conjugate of deacetyl-KE-298, was detected. Neither deacetyl-KE-298-amino acid mixed disulfide nor any disulfide of the drugs was found. Though a thiol-containing drug generally remains in the body due to the formation of mixed disulfide with protein, no evidence of retained radioactivity was found in any tissues after the administration of [14C]KE-298. Further, in the ex vivo studies of plasma protein binding, the formation of drug-protein conjugate was scarcely detected. These results suggest that the metabolic pattern of deacetyl-KE-298 is different from that of common thiol-containing drugs, and that the reactivity of the thiol moiety of deacetyl-KE-298 to protein is extremely low. This property of deacetyl-KE-298 may be principally responsible for the nonaccumulation of radioactivity in the tissues after the administration of [14C]KE-298.

Identification of Metabolites of KE-298, a New Antirheumatic Drug, and Its Physiological Properties in Rats.