New metabolic pathways of alpha-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 [(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.
Schupke
H
H
Department of Metabolism and Development, elbion AG, Radebeul, Germany. Hubert.Schupke@elbion.de
Hempel
R
R
Peter
G
G
Hermann
R
R
Wessel
K
K
Engel
J
J
Kronbach
T
T
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
D008063:Thioctic Acid