title: Formation of a disulfide protein conjugate of the SH-group-containing metabolite (M-I) of esonarimod (KE-298) and its elimination in rats.
abstract: The reactivity of the thiol moiety of the active main metabolite (M-I) of esonarimod (KE-298), a novel anti-rheumatic agent, was investigated in rats. After repeated oral administration of 14C-KE-298, the radioactivity decreased rapidly and no tendency towards accumulation was found, in marked contrast to other common SH-group-containing drugs. At 30 min after intravenous administration of 14C-M-I to rats, the concentration of the 14C-M-I plasma protein conjugate in plasma was extremely low at 0.143 nmol mL(-1) (0.66% of total plasma radioactivity). The 14C-M-I plasma protein conjugate that formed in rat plasma was mixed disulfide with plasma protein. After intravenous administration of synthetic 14C-M-I plasma protein conjugate to rats, the radioactivity in plasma decreased rapidly, with the terminal half-life at 6.90 h. In-vitro, the 14C-M-I plasma protein conjugate was readily dissociated by the endogenous thiol compounds, cysteine and glutathione. These results suggest that the reactivity of the thiol moiety of M-I is extremely low. Furthermore, the 14C-M-I plasma protein conjugate decreased rapidly in-vivo, which would be related to interaction with endogenous thiol compounds. These properties of M-I are principally responsible for the zero accumulation in rat tissues. KE-298 could therefore be expected to have reduced adverse effects compared with other SH-group-containing anti-rheumatic drugs.
authors: Drug Metabolism and Toxicology Research Center, Taisho Pharmaceutical Co, Ltd, Saitama, Japan. m.hasegawa@po.rd.taisho.co.jp
authors: Masatoshi
authors: M
authors: Hasegawa
authors: Naoko
authors: N
authors: Omi
authors: Hiromi
authors: H
authors: Endo
authors: Hideo
authors: H
authors: Yoshida
authors: Shohei
authors: S
authors: Higuchi
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D001011:Aorta / Q000378:metabolism; D001665:Binding Sites; D001798:Blood Proteins / Q000378:metabolism; D002250:Carbon Radioisotopes; D003545:Cysteine / Q000737:chemistry / Q000378:metabolism; D005978:Glutathione / Q000737:chemistry / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D010666:Phenylpropionates / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D012867:Skin / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D018501:Antirheumatic Agents; D001798:Blood Proteins; D002250:Carbon Radioisotopes; D010666:Phenylpropionates; D013438:Sulfhydryl Compounds; D005978:Glutathione; D003545:Cysteine; C078547:esonarimod