Enantiomer-selective pharmacokinetics, oral bioavailability, and sex effects of various alpha-lipoic acid dosage forms

Abstract

The present study aimed to examine the enantiomer-selective pharmacokinetics (PK), relative bioavailability (Frel), and sex effects of various oral dosage forms of racemic alpha-lipoic acid (ALA). In an open-label, randomized, four-period, four-sequence crossover study, 24 healthy adult subjects (12 males and 12 females) received single doses of 600 mg of ALA in fasted state at four different occasions as follows: three 200 mg tablets (T 200); two 300 mg tablets (T 300); one 600 mg tablet (T 600); and a racemic ALA solution (OS). All tablet formulations (Thioctacid HR) were considered test treatments, while the OS (Thioctacid, 600 T) served as the reference treatment. Serial blood samples were collected over 8 hours postdose to quantify R-(+)- and S-(−)-ALA enantiomer plasma concentrations for the PK evaluation. The maximum observed plasma concentration (Cmax) and total exposure (area under the curve [AUC]0–t) were compared between treatments by analysis of variance. Weight-normalized Cmax and the AUC data of male and female study subjects were applied to examine the presence of sex effects. All treatments displayed rapid absorption of both enantiomers with median time to maximum concentration (tmax) values ranging from 0.33–0.5 hours. The Frel of all tablet formulations was comparable, with R-(+)-enantiomer Cmax test/reference ratios ranging from 36% (T 600) to 43% (T 200), and R-(+)-enantiomer AUC test/reference ratios ranging from 64% (T 600) to 79% (T 300), indicating a favorable Frel of all tablet formulations, especially in terms of the total extent of absorption (AUC). An examination of weight-normalized female/male Cmax and AUC sex ratios for both ALA enantiomers indicated the absence of a significant sex effect for Cmax, as well as 20%–26% and 25%–32% higher R-(+)- and S-(−)-ALA enantiomer AUC outcomes in females when compared to males. The observed modest sex effect was comparable for both ALA enantiomers and across all formulations, and it did not appear to require a dose adjustment in clinical practice.

Нові Можливості Застосування Альфа-Ліпоєвої Кислоти: Роль Енантіомерів

“…Отмечено (Hermann R., Ziegler D. et al, 2014), что пиковые C max концентрации в плазме R(+)энантиомеров рацемической смеси АЛК, применяемой в дозировке 600 мг однократно в виде трех таблеток по 200 мг, или 2 таблеток по 300 мг, или Огляд літератури /Literature Review/ одной таблетки 600 мг, или раствора 600 мг, на 36-43 % выше, чем у S-энантиомеров. А общая экспозиция R(+)-энантиомеров АЛК, рассчитанная по динамике концентрации в плазме (AUC, площади под кривой) показала, что R(+)-энантиомеры АЛК от 64 % (для дозы 600 мг в одной таблетке) до 79 % (для дозы 300 мг, две таблетки) имеют большую AUC, чем S-энантиомеры.…”

“…Авторы установили почти в два раза более высокую биодоступность R(+)-энантиомера по сравнению с формой S(-) и указывают на существование активного транспортер-опосредованного кишечного поглощения именно R(+)-формы АЛК, которое недоступно для S(-)-энантиомера АЛК. Тем не менее, по мнению авторов, эта гипотеза должна быть рассмотрена в специальных исследованиях [33].…”

Supplementation with Phycocyanobilin, Citrulline, Taurine, and Supranutritional Doses of Folic Acid and Biotin—Potential for Preventing or Slowing the Progression of Diabetic Complications

“…Phase II inducers, via activation of the nrf2 transcription factor, boost the expression of a range of antioxidants enzymes, and also induce the enzyme that is rate-limiting for glutathione synthesis [275,276]. Lipoic acid—particularly its physiological R enantiomer, which is transported more efficiently [277]—is outstanding in this regard, as it has favorable pharmacokinetics, and has been shown to be clinically useful in management of diabetic neuropathy [278,279,280,281]. The glutathione-boosting efficacy of phase 2 inducers can be enhanced by concurrent administration of N-acetylcysteine, a delivery form for cysteine.…”

Liposomal Encapsulated Alpha-Lipoic Acid, Benfotiamine and Curcumin Prevent Overfeeding Mediated Increases in Waist Circumference

“…We hypothesize that 28 days of dietary liposomal encapsulated CUR, ALA and BEN will result in increased circulating CUR and ALA and attenuate insulin resistance induced by high fat diet and exercise abstention in healthy, usually active college aged adults. A common limitation of CUR, ALA and thiamine supplementation is poor bioavailability after oral consumption 67,77,78 . However, it is possible to improve the bioavailability of CUR when administered via liposomes or micelles 44 , and thiamine when administered as BEN 61 .…”