Identification of Metabolites of KE-298,a New Antirheumatic Drug, and Its Physiological Properties in Rats
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概要
- 論文の詳細を見る
To characterize the pharmacokinetic properties of a new antirheumatic drug, KE-298,the metabolic fate of [^<14>C] labeled KE-298 in rats was investigated, focussing especially on the identification of metabolites and its physiological properties. [^<14>C] 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 [^<14>C] 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 [^<14>C] KE-298.
- 公益社団法人日本薬学会の論文
- 1996-03-15
著者
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Hasegawa Masatoshi
Department Of Drug Metabolism Research Center Taisho Pharmacetutical Co. Ltd.
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Kohno Yoshiro
大正製薬(株)開発研究所薬物動態研究室
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Kohno Yoshiro
Drug Metabolism Laboratory Taisho Pharmaceutical Co. Ltd.
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Suwa T
大正製薬(株)開発研究所薬物動態研究室
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Suwa Toshio
Dept.of Biochemistry Tokyo College Of Pharmacy:(present Address) Research Center Taisho Pharmaceutic
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Yoshida H
Lab. Of Food & Nutritional Sciences Dep. Of Nutritional Sci. Kobe-gakuin Univ.
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YOSHIDA Hideo
Drug Metabolism Laboratory, Taisho Pharmaceutical Co., Ltd.
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ENDO Hiromi
Drug Metabolism Laboratory, Taisho Pharmaceutical Co., Ltd.
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HASEGAWA Masatoshi
Drug Metabolism Laboratory, Taisho Pharmaceutical Co., Ltd.
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YAMAGUCHI Jyunichi
Drug Metabolism Laboratory, Taisho Pharmaceutical Co., Ltd.
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TOMISAWA Kazuyuki
Drug Metabolism Laboratory, Taisho Pharmaceutical Co., Ltd.
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SUWA Toshio
Drug Metabolism Laboratory, Taisho Pharmaceutical Co., Ltd.
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Endo H
Department Of Drug Metabolism Research Center Taisho Pharmacetutical Co. Ltd.
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Tomisawa Kazuyuki
Drug Metabolism Laboratory Taisho Pharmaceutical Co. Ltd.
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Yamaguchi Jyunichi
Drug Metabolism Laboratory Taisho Pharmaceutical Co. Ltd.
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