Enantioselective Pharmacokinetics of α-Lipoic Acid in Rats

Uchida, Ryota; Okamoto, Hinako; Ikuta, Naoko; Terao, Keiji; Hirota, Takashi

doi:10.3390/ijms160922781

Cited by 30 publications

(27 citation statements)

References 41 publications

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“…It is not easy to evaluate the pharmacological effects of an antioxidant, but the present study highlighted the efficacy of a chronic discontinuous treatment with lipoic acid once the metabolic disturbances induced by the fructose feeding had been installed in the rats. AL, when absorbed, has a very short half-life (30-40 min after oral and 12 min after intravenous administrations) [66], being rapidly intracellularly uptaken, metabolized, and renally excreted [19,67]. In this context, the benefits of our chronic discontinuous treatment may be partially assigned to dihydrolipoic acid (DHLA), the intracellular active metabolite of AL, which can recycle for a while the AL/DHLA system [17,67,68].…”

Section: Discussionmentioning

confidence: 99%

Impact of Alpha-Lipoic Acid Chronic Discontinuous Treatment in Cardiometabolic Disorders and Oxidative Stress Induced by Fructose Intake in Rats

et al. 2019

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Insulin resistance (IR) and cardiometabolic disorders are the main consequences of today's alimentary behavior. This study evaluates the effects of a chronic-discontinuous treatment with alpha-lipoic acid (AL), an antioxidant substance that improves glycemic control associated with diabetes mellitus, on metabolic disorders and plasma oxidative stress induced by fructose intake, in rats. Sprague-Dawley rats (48 animals) were randomized into two series (n = 24): rats fed with standard chow or with standard chow supplemented with 60% fructose. In each of the two series, for 2 weeks/month over 12 weeks, a group of rats (n = 12) was intraperitoneally injected with NaCl 0.9%, and a second group (n = 12) received AL 50 mg/kg/day. Body weight, glycemia, and systolic blood pressure were monitored throughout the study. After 12 weeks, IR, plasma lipoproteins, uric acid, transaminase activities, and oxidative stress markers were assessed. The high fructose-enriched diet induced cardiometabolic disorders (hypertension, hyperglycemia, IR and dyslipidemia), an increase in uric acid concentration, transaminase activities and C-reactive protein level. This diet also enhanced plasma products of lipid and protein oxidation, homocysteine level, and decreased GSH/GSSG ratio. In this field, there is evidence to indicate that oxidative stress plays an important role in the etiology of diabetic complications. AL discontinuous treatment prevents the metabolic disorders induced by fructose intake, reduced plasma lipid and protein oxidation-products, and restored the GHS/GSSG ratio. Our study proves a promising potential of the chronic-discontinuous treatment of AL and highlights the pleiotropic effects of this antioxidant substance in metabolic disorders such as diabetes.

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Section: Discussionmentioning

confidence: 99%

Impact of Alpha-Lipoic Acid Chronic Discontinuous Treatment in Cardiometabolic Disorders and Oxidative Stress Induced by Fructose Intake in Rats

et al. 2019

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“…Significant difference in concentration in the basal side was observed only at two time point after 120 min (the low- and middle-concentration groups). However, we considered no enantiolectivity on the LA transport, because the difference was much smaller than that observed in our animal testing [ 15 ]. Permeability rates were linearly correlated ( R 2 > 0.9992) with the initial concentrations of LA at the apical side ( Figure 2 A,B), indicating that transport of LA across Caco-2 cells was not saturated in the concentration range used in this study.…”

Section: Resultsmentioning

confidence: 99%

“…We previously reported the enantioselective pharmacokinetics of LA in rats [ 15 ]. In that study, we observed that the F h and F a and/or F g of transport from the gastrointestinal tract to the systemic circulation were implicated in these enantioselective pharmacokinetics.…”

Section: Resultsmentioning

confidence: 99%

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Investigation of Enantioselective Membrane Permeability of α-Lipoic Acid in Caco-2 and MDCKII Cell

Uchida

Okamoto

Ikuta

et al. 2016

IJMS

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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.

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“…5). In the pharmacokinetics studies, it was reported that the maximum plasma concentrations in mice after the oral administration of ALA at 50 and 100 mg/kg were 7.6 ± 1.4 µg/mL (around 36 µM) and 30.9 ± 1.4 µg/mL (around 150 µM), respectively, 38) and that the half-life was around 27 min after the oral administration at 20 mg/kg in rats. 39) Although the actual plasma concentration of ALA in the present study using mice constantly ingesting ALA with the diet was not measured, our results suggested that the mechanisms for the beneficial effects of chronic ALA administration on the clonidine-induced vasodilation could involve the action to aortas.…”

Section: Discussionmentioning

confidence: 99%

Chronic Treatment with α-Lipoic Acid Improves Endothelium-Dependent Vasorelaxation of Aortas in High-Fat Diet-Fed Mice

Takenouchi

Tsuboi

Ohsuka

et al. 2019

Biological & Pharmaceutical Bulletin

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α-Lipoic acid (ALA) is used as a dietary supplement and known as an anti-oxidant. The present study aimed to examine whether ALA improves endothelial dysfunction in high-fat diet-fed obese mice. After feeding a high-fat diet to Institute of Cancer Research (ICR) mice for 4 weeks, the mice were maintained with a high-fat diet (group HF) or a high-fat diet containing ALA (25 mg/d, group HF ALA) for an additional 20 weeks. Age-matched normal diet-fed mice were also used (group Normal). Chronic oral treatment with ALA did not affect various plasma parameters or body weights. As compared with the aortas of Normal mice, those from HF mice showed impaired endothelium-dependent relaxation in response to clonidine. However, such an impairment was not observed in the aortas from HF ALA mice. The plasma levels of thiobarbituric acid reactive substances, an indicator of oxidative stress, were significantly decreased in HF ALA mice compared with HF mice, confirming the anti-oxidative effects of ALA. In addition, when the impaired clonidine-induced vasorelaxation of aortas from normal mice under high glucose conditions was used as a model of acute oxidative stress, the vasorelaxation responses were improved in the presence of ALA at 100 µM. Our results suggested that the chronic oral administration of ALA improves endothelial dysfunction in high-fat diet-fed obese mice possibly through the reduction in oxidative stress in vivo.

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Enantioselective Pharmacokinetics of α-Lipoic Acid in Rats

Cited by 30 publications

References 41 publications

Impact of Alpha-Lipoic Acid Chronic Discontinuous Treatment in Cardiometabolic Disorders and Oxidative Stress Induced by Fructose Intake in Rats

Impact of Alpha-Lipoic Acid Chronic Discontinuous Treatment in Cardiometabolic Disorders and Oxidative Stress Induced by Fructose Intake in Rats

Investigation of Enantioselective Membrane Permeability of α-Lipoic Acid in Caco-2 and MDCKII Cell

Chronic Treatment with α-Lipoic Acid Improves Endothelium-Dependent Vasorelaxation of Aortas in High-Fat Diet-Fed Mice

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