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

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 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.

Small‐Molecule Targeting of the Mitochondrial Compartment with an Endogenously Cleaved Reversible Tag

“…[13][14][15] In a separate experiment, the release of free LipAc was monitored and quantified by HPLC-UV detection. After 60 min approximately 60 mol % of the revMitoLipAc (2) had been converted into LipAc (Figure 1 A, black bars), whereas 40 mol % was not detected, due either to incomplete extraction or to subsequent metabolism into LipAc metabolites, such as dimethyl lipoic acid, [16] which could not be detected. Again, no cleavage reaction occurred when mitochondria were pre-incubated with benomyl (250 mm; Figure 1 A, white bars).…”

(R)-α-Lipoic acid reverses the age-related loss in GSH redox status in post-mitotic tissues: evidence for increased cysteine requirement for GSH synthesis

“…Because the liver is the initial and the primary site of LA uptake and reduction, it is likely that both oxidized and reduced forms of LA are quickly available in the plasma for uptake by the brain and heart [36,37]. Although the exact ratio between LA and DHLA in the brain and the heart is not known, it is unlikely that direct antioxidant effects of DHLA are fully responsible for the observed improvements in GSH redox state.…”

Determination of lipoic acid in rat plasma by LC‐MS/MS with electrospray ionization: Assay development, validation and application to a pharamcokinetic study

“…In humans lipoic acid is rapidly absorbed, as indicated by the t max of 0.8 h, with a limited oral bioavailability (primarily due to high first-pass metabolism) and 0.5 h elimination half-life (Teichret et al, 1998(Teichret et al, , 2003. The pharmacokinetic disposition and metabolic pathway of lipoic acid were well characterized in humans (Schupke et al, 2002;Teichert et al, 2003). The pharmacokinetics of lipoic acid and its metabolites showed no differences following multiple dose administration in humans.…”