ABSTRACT
Introduction: Structure, Stereochemistry, and Mechanisms of Action of Alpha Lipoic Acid................................................................................... 236
Structure, Physical Properties, Stability, and Stereochemistry of Alpha Lipoic Acid and Dihydrolipoic Acid ........................................................... 239
Stability of Dihydrolipoic Acid In Vitro and during Sample Preparation ...... 240 Baseline Levels of R-Dihydrolipoic Acid in Human Plasma.......................... 240 Enzymatic Reduction of Alpha Lipoic Acid: Is Dihydrolipoic Acid an In Vivo Plasma Metabolite of Alpha Lipoic Acid?................................ 242
Animal and Human Plasma Pharmacokinetics of Rac-Dihydrolipoic Acid .......................................................................... 246
Plasma Pharmacokinetics of R-(þ)-a Lipoic Acid in Humans....................... 248 Materials........................................................................................................... 249
Analytical Equipment and Methods ................................................................ 249 Plasma Collection and Comparison of Anticoagulants ................................... 250 Comparisons of High-Performance Liquid Chromatography Methods of Analysis .................................................................................... 251
Results and Discussion: A Reevaluation of the Stability of R-Dihydrolipoic Acid .............................................................................. 252
Pharmacokinetics of Na-RLA versus R-(þ)-a Lipoic Acid and R-Dihydrolipoic Acid............................................................................ 254
Abbreviations ................................................................................................... 259 References ........................................................................................................ 261
Alpha lipoic acid (ALA) is a medium chain (C8) fatty acid with vicinal sulfur atoms at C6 and C8 existing either as free sulfhydryls (DHLA) or linked via an intramolecular disulfide (ALA). The C6 atom (alternatively designated as C3 of the dithiolane ring) of the octanoic acid chain is chiral and the molecules exist as four enantiomers (R-(þ)-LA, S-()-LA, R-()-DHLA, and S-(þ)-DHLA) (Figure 10.1) and two racemic mixtures (rac-ALA¼þ=ALA¼ (RS)-ALA and rac-DHLA¼ (þ=)-ALA¼RS-DHLA). These six forms of lipoic acid have
H
∗
S S R-(+)-ALA [1200-22-2]
O
OH
S S
H S-()-ALA [1077-27-6] O
O
OH
OH
S -(+)-DHLA [98441-85-1]HSSH
∗
H OH
OR -()-DHLA[119365-69-4] H
SH HS
Oxidized Reduced
FIGURE 10.1 Three dimensional molecular diagrams depicting both the absolute configurations (R and S) which are mirror images and the change in specific rotations from (+) to () when RLA is reduced to R-DHLA of () to (+) when SLA is reduced to S-DHLA. The diagrams are useful in conceptualizing how one enantiomer can react differently than its mirror image with a receptor, transporter, signaling molecule, protein or enzyme in vivo. Only RLA is naturally occurring and proposed to be the eutomeric form of ALA.
