title: Identification of metabolites of KE-298, a new antirheumatic drug, and its physiological properties in rats.
abstract: 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.
authors.affiliation: Drug Metabolism Laboratory, Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Yoshida
authors.forename: Y
authors.initials: Y
authors.lastname: Kohno
authors.forename: H
authors.initials: H
authors.lastname: Endo
authors.forename: M
authors.initials: M
authors.lastname: Hasegawa
authors.forename: J
authors.initials: J
authors.lastname: Yamaguchi
authors.forename: K
authors.initials: K
authors.lastname: Tomisawa
authors.forename: T
authors.initials: T
authors.lastname: Suwa
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000493:pharmacokinetics*; D001711:Biotransformation; D001798:Blood Proteins / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D010666:Phenylpropionates / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
chemical_list: D018501:Antirheumatic Agents; D001798:Blood Proteins; D010666:Phenylpropionates; C078547:esonarimod