M. Hasegawa, N. Omi, H. Endo
Apr 1, 2002
Citations
0
Influential Citations
0
Citations
Quality indicators
Journal
Journal of Pharmacy and Pharmacology
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.