METABOLISM OF EBSELEN (DR-3305) : RELATION TO THE ANTIOXIDANT ACTIVITY

Ebselen, 2-phenyl-1, 2-benzisoselenazol-3(2H)-one, is a selenoorganic antioxidant with glutathione peroxidase (GSH-Px)-like activity. After oral administration, ebselen reacted with thiol group of plasma proteins (albumin) in rat, forming a selenosulfide complex (Se-S complex) and unchanged ebselen was hardly found. We focused on the GSH-Px-like activity of the complex itself. Se-S complex prepared from ebselen and BSA showed GSH-Px-like activity towards hydroperoxides. Other selenosulfide and diselenide derivatives as well as ebselen showed similar GSH-Px-like activity to that of the complex. Ebselen is extensively metabolized in vivo, and authentic samples of main urinary and biliary metabolites have no antioxidant activities. We therefore investigated metabolic patterns in tissues and found two polar unknown metabolites in rat fat. These metabolites were isolated, analyzed by HPLC/MS, and identified as ebselen Se-oxide (SeOx) and 2-(methylseleninyl)benzanilide (Se(O)Me). SeOx can be reduced back to ebselen by reductant such as GSH. Interestingly, the isolated Se(O)Me afforded ebselen and its Se-oxide in a solution left standing. Either metabolite can revert to ebselen. Se-S complex as well as these metabolites are possibly responsible for the pharmacological activity shown by oral dose of ebselen in vivo.