Abstract
α-Lipoic acid (LA) contains a chiral carbon and exists as two enantiomers (R-α-lipoic acid (RLA) and S-α-lipoic acid (SLA)). We previously demonstrated that oral bioavailability of RLA is better than that of SLA. This difference arose from the fraction absorbed multiplied by gastrointestinal availability (Fa × Fg) and hepatic availability (Fh) in the absorption phase. However, it remains unclear whether Fa and/or Fg are involved in enantioselectivity. In this study, Caco-2 cells and Madin–Darby canine kidney strain II cells were used to assess the enantioselectivity of membrane permeability. LA was actively transported from the apical side to basal side, regardless of the differences in its steric structure. Permeability rates were proportionally increased in the range of 10–250 µg LA/mL, and the permeability coefficient did not differ significantly between enantiomers. Hence, we conclude that enantioselective pharmacokinetics arose from the metabolism (Fh or Fg × Fh), and definitely not from the membrane permeation (Fa) in the absorption phase.
Highlights
Introduction α-Lipoic acid (LA; 5-(1,2-dithiolan-3-yl) pentanoic acid) is a sulfur-containing organic acid derived from octanoic acid
We previously reported the enantioselective pharmacokinetics of LA in rats [15]
We found that the transport of LA across the monolayers of two cell types was not enantioselective
Summary
RLA-Na (purity of >98.0%) was purchased from Toyo Hakko Co., Ltd. (Obu, Japan) and SLA-Na (purity of >85.0%) was supplied from Changshu Fushilai Medicine and Chemical Co., Ltd. (Changshu, China). RLA-Na (purity of >98.0%) was purchased from Toyo Hakko Co., Ltd. (Obu, Japan) and SLA-Na (purity of >85.0%) was supplied from Changshu Fushilai Medicine and Chemical Co., Ltd. Rac-LA (purity of >98.0%) and Dulbecco’s Modified Eagle Medium (DMEM) were purchased from Sigma-Aldrich Production GmbH (Buchs, Switzerland), and Rac-LA-d5 (purity of >98.0%) was purchased from Toronto Research Chemicals Inc. Minimum essential medium (MEM), L-glutamine, penicillin-streptomycin, fetal bovine serum (FBS), and Hank’s balanced salt solution (HBSS) were purchased from ThermoFisher Science (Waltham, MA, USA). Antibiotic-Antimycotic Mixed Stock Solution (100ˆ) was purchased from Nacalai Tesque Inc. All other chemicals and reagents were commercially available and were of analytical grade or higher
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