Plasma Kinetics, Metabolism, and Urinary Excretion of Alpha‐Lipoic Acid following Oral Administration in Healthy Volunteers

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Abstract
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 β‐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 β‐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.