New metabolic pathways of α-lipoic acid

The excretion and biotransformation of rac-alpha -lipoic acid (LA), which is used for the symptomatic treatment of diabetic polyneuropathy, were investigated following single oral dosing of [C-14]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 beta -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 P-oxidation, predominantly in mice.