title: New metabolic pathways of alpha-lipoic acid.
abstract: 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 [(14)C]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 beta-oxidation, predominantly in mice.
authors.affiliation: Department of Metabolism and Development, elbion AG, Radebeul, Germany. Hubert.Schupke@elbion.de
authors.forename: H
authors.initials: H
authors.lastname: Schupke
authors.forename: R
authors.initials: R
authors.lastname: Hempel
authors.forename: G
authors.initials: G
authors.lastname: Peter
authors.forename: R
authors.initials: R
authors.lastname: Hermann
authors.forename: K
authors.initials: K
authors.lastname: Wessel
authors.forename: J
authors.initials: J
authors.lastname: Engel
authors.forename: T
authors.initials: T
authors.lastname: Kronbach
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D006801:Humans; D013058:Mass Spectrometry; D051379:Mice; D010084:Oxidation-Reduction; D051381:Rats; D012015:Reference Standards; D008063:Thioctic Acid / Q000493:pharmacokinetics* / Q000652:urine
chemical_list: D008063:Thioctic Acid