Plasma kinetics, metabolism, and urinary excretion of alpha-lipoic acid following oral administration in healthy volunteers.
R(+)-alpha-lipoic acid is a natural occurring compound that acts as an essential cofactor for certain dehydrogenase complexes. The redox couple alpha-lipoic acid/dihydrolipoic acid possesses potent antioxidant activity. Exogenous racemic alpha-lipoic acid orally administered for the symptomatic treatment of diabetic polyneuropathy is readily and nearly completely absorbed, with a limited absolute bioavailability of about 30% caused by high hepatic extraction. Although the pharmacokinetics of the parent drug have been well characterized in humans, relatively little is known regarding the excretion of alpha-lipoic acid and the pharmacokinetics of any metabolites in humans. In the present study, plasma concentration-time courses, urinary excreted amounts, and pharmacokinetic parameters of alpha-lipoic acid metabolites were evaluated in 9 healthy volunteers after multiple once-daily oral administration of 600 mg racemic alpha-lipoic acid. The primary metabolic pathways of alpha-lipoic acid in man, S-methylation and beta-oxidation, were quantitatively confirmed by an HPLC-electrochemical assay newly established prior to the beginning of this study. Major circulating metabolites were the S-methylated beta-oxidation products 4,6-bismethylthio-hexanoic acid and 2,4-bismethylthio-butanoic acid, whereas its conjugated forms accounted for the major portion excreted in urine. There was no statistically significant difference in the pharmacokinetic parameters Cmax, AUC, and tmax between day 1 and day 4. Despite the prolonged half-lives of the major metabolites compared to the parent drug, no evidence of accumulation was found. Mean values of 12.4% of the administered dose were recovered in the urine after 24 hours as the sum of alpha-lipoic acid and its metabolites. The results of the present study revealed that urinary excretion of alpha-lipoic acid and five of its main metabolites does not play a significant role in the elimination of alpha-lipoic acid. Therefore, biliary excretion, further electrochemically inactive degradation products, and complete utilization of alpha-lipoic acid as a primary substrate in the endogenous metabolism should be considered.
Teichert
Jens
J
Institute of Clinical Pharmacology, University of Leipzig, Institute of Clinical Pharmacology, Haertelstr. 16-18, 04107 Leipzig, Germany.
Hermann
Robert
R
Ruus
Peter
P
Preiss
Rainer
R
D000284:Administration, Oral; D000368:Aged; D000704:Analysis of Variance; D019540:Area Under Curve; D005260:Female; D006801:Humans; D016014:Linear Models; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology; D008875:Middle Aged; D018709:Statistics, Nonparametric; D008063:Thioctic Acid / Q000008:administration & dosage / Q000097:blood* / Q000652:urine*
D008063:Thioctic Acid