ABSTRACT
Introduction...................................................................................................... 271 Metabolic Pathways of a-Lipoic Acid ............................................................ 272 Pharmacokinetic Properties of a-Lipoic Acid and Its Metabolites in Healthy Volunteers .................................................................................. 274 Single-Dose Trials........................................................................................ 274 Multiple-Dose Trials .................................................................................... 276 Summary ...................................................................................................... 279
Pharmacokinetic Properties of a-Lipoic Acid and Its Metabolites in Patients with Renal Impairment .............................................................. 280 Patients with Severe Renal Dysfunction...................................................... 280 Patients with End-Stage Renal Disease ....................................................... 284 Summary ...................................................................................................... 288
Conclusions...................................................................................................... 288 References ........................................................................................................ 290
Alpha-lipoic acid (1,2-dithiolane-3-pentanoic acid), also known as thioctic acid, contains an intramolecular disulfide bond that can be enzymatically reduced in vivo resulting in the formation of two highly reactive vicinal sulfhydryl groups. Due to the low negative redox potential (0.32 V) the reduced form of dihydrolipoic acid (6,8-dimercapto-octanoic acid) can regenerate ascorbate directly and is capable of regenerating endogenous thiols involved in physiological antioxidant
redox systems such as cysteine and glutathione. The naturally occurring redox couple containing the R-enantiomer of a-lipoic=dihydrolipoic acid is covalently bound to a lysine residue forming an essential lipoamide that functions as a coenzyme of E2 subunit of four mitochondrial multienzyme complexes, e.g., the pyruvate dehydrogenase. Exogenously administered a-lipoic acid is reduced intracellularly by several enzymes and released as dihydrolipoic acid into the extracellular milieu. Racemic a-lipoic acid has been used in Germany in the treatment of diabetic polyneuropathy for many years. Because a-lipoic acid has been reported to have a number of potentially beneficial effects in both prevention and treatment of free-radical mediated diseases, numerous preclinical and clinical trials especially for the therapy of type-2 diabetes-induced diabetic polyneuropathy have been conducted. The efficacy of a-lipoic acid treatment on neuropathic disorders has been contradictorily discussed because the results of the individual trials varied and a conclusive interpretation is difficult.
