Formation of a disulfide protein conjugate of the SH-group-containing metabolite (M-I) of esonarimod (KE-298) and its elimination in rats

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.