TY - JOUR T1 - New Metabolic Pathways of α-Lipoic Acid JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 855 LP - 862 VL - 29 IS - 6 AU - Hubert Schupke AU - Roland Hempel AU - Gernot Peter AU - Robert Hermann AU - Klaus Wessel AU - Jürgen Engel AU - Thomas Kronbach Y1 - 2001/06/01 UR - http://dmd.aspetjournals.org/content/29/6/855.abstract N2 - The excretion and biotransformation ofrac-α-lipoic acid (LA), which is used for the symptomatic treatment of diabetic polyneuropathy, were investigated following single oral dosing of [14C]LA to mice (30 mg/kg), rats (30 mg/kg), dogs (10 mg/kg), and unlabeled LA to humans (600 mg). More than 80% of the radioactivity given was renally excreted. Metabolite profiles obtained by radiometric high-performance liquid chromatography revealed that LA was extensively metabolized irrespective of the species. Based on a new on-line liquid chromatography/tandem mass spectroscopy assay developed for negative ions, LA and a total of 12 metabolites were identified. Mitochondrial β-oxidation played the paramount role in the metabolism of LA. Simultaneously, the circulating metabolites were subjected to reduction of the 1,2-dithiolane ring and subsequent S-methylation. In addition, evidence is given for the first time that the methyl sulfides formed were partly oxidized to give sulfoxides, predominantly in dogs. The disulfoxide of 2,4-bismethylmercapto-butanoic acid, the most polar metabolite identified, was the major metabolite in dogs. Furthermore, new data are presented that suggest conjugation with glycine occurred as a separate metabolic pathway in competition with β-oxidation, predominantly in mice. The American Society for Pharmacology and Experimental Therapeutics ER -