IDENTIFICATION OF METABOLITES OF KE-298, A NEW ANTIRHEUMATIC DRUG, AND ITS PHYSIOLOGICAL-PROPERTIES IN RATS

To characterize the pharmacokinetic properties of a new antirheumatic drug, KE-298, the metabolic fate of [C-14]labeled KE-298 in rats was i nvestigated, focussing especially on the identification of metabolites and its physiological properties, [C-14]RE-298 was rapidly and almost completely absorbed after oral administration, and was well distribut ed throughout the body. In plasma, only a small amount of unchanged KE -298 was detected and the major component was an active metabolite, de acetyl-KE-298, which accounted for approximately 50% of the radioactiv ity in the plasma, Further evidence was obtained by H-1-NMR analysis t hat deacetyl-KE-298 existed as ketone-thiol and thiohemiacetal forms i n a tautomeric equilibrium, As the second main metabolite in plasma, S -methyl-KE-298, a methyl conjugate of deacetyl-KE-298, was detected. N either 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 [C-14]RE-298. Further, in the ex vivo studies of pla sma protein binding, the formation of drug-protein conjugate was scarc ely detected, These results suggest that the metabolic pattern of deac etyl-KE-298 is different from that of common thiol-containing drugs, a nd that the reactivity of the thiol moiety of deacetyl-KE-298 to prote in is extremely low, This property of deacetyl-KE-298 may be principal ly responsible for the nonaccumulation of radioactivity in the tissues after the administration of [C-14]KE-298.