BACKGROUND The racemic mixture, RS-(+/-)-alpha-lipoic acid (rac-LA) has been utilized clinically and in a variety of disease models. Rac-LA and the natural form, R-lipoic acid (RLA), are widely available as nutritional supplements, marketed as antioxidants. Rac-LA sodium salt (NaLA) or rac-LA potassium salt (KLA) has been used to improve the aqueous solubility of LA. STUDY RATIONALE Several in vitro and animal models of aging and age-related diseases have demonstrated efficacy for the oral solutions of LA salts in normalizing age-related changes to those of young animals. Other models and studies have demonstrated the superiority of RLA, the naturally occurring isomer over rac-LA. Despite this, RLA pharmacokinetics (PK) is not fully characterized in humans, and it is unknown whether the concentrations utilized in animal models can be achieved in vivo. Due to its tendency to polymerize, RLA is relatively unstable and suffers poor aqueous solubility, leading to poor absorption and low bioavailability. A preliminary study demonstrated the stability and bioavailability were improved by converting RLA to its sodium salt (NaRLA) and pre-dissolving it in water. The current study extends earlier findings from this laboratory and presents PK data for the 600-mg oral dosing of 12 healthy adult subjects given NaRLA. In addition, the effect of three consecutive doses was tested on a single subject relative to a one-time dosing in the same subject to determine whether plasma maximum concentration (Cmax) and the area under the plasma concentration versus time curve (AUC) values were comparable to those in animal studies and those achievable via intravenous infusions in humans. METHODS Plasma RLA was separated from protein by a modification of a published method. Standard curves were generated from spiking known concentrations of RLA dissolved in ethanol and diluted in a phosphate-buffered saline (PBS) into each individual's baseline plasma to account for inter-individual differences in protein binding and to prevent denaturing of plasma proteins. Plasma RLA content was determined by the percent recovery using high-performance liquid chromatography (electrochemical/coulometric detection) (HPLC/ECD). RESULTS As anticipated from the preliminary study, NaRLA is less prone to polymerization, completely soluble in water, and displays significantly higher Cmax and AUC values and decreased time to maximum concentration (Tmax) and T1/2 values than RLA or rac-LA. In order to significantly extend Cmax and AUC, it is possible to administer three 600-mg RLA doses (as NaRLA) at 15-minute intervals to achieve plasma concentrations similar to those from a slow (20-minute) infusion of LA. This is the first study to report negligible unbound RLA even at the highest achievable plasma concentrations.

中文翻译：

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R-（+）-硫辛酸以R-（+）-硫辛酸钠的形式给药于健康人的血浆药代动力学。

背景技术外消旋混合物RS-（+/-）-α-硫辛酸（rac-LA）已经在临床上和在各种疾病模型中使用。Rac-LA和天然形式的R-硫辛酸（RLA）作为营养补充剂广泛出售，作为抗氧化剂出售。Rac-LA钠盐（NaLA）或rac-LA钾盐（KLA）已用于改善LA的水溶性。研究理由一些衰老和与年龄有关的疾病的体外和动物模型已证明，LA盐口服溶液能使与年幼动物的年龄相关变化正常化。其他模型和研究表明，天然存在的异构体RLA优于rac-LA。尽管如此，RLA药代动力学（PK）尚未在人类中充分表征，尚不清楚在动物模型中使用的浓度能否在体内达到。由于其聚合的趋势，RLA相对不稳定并且水溶性差，导致吸收差和生物利用度低。初步研究表明，将RLA转化为其钠盐（NaRLA）并将其预先溶解在水中可提高稳定性和生物利用度。当前的研究扩展了该实验室的早期发现，并提供了接受NaRLA治疗的12位健康成人受试者600毫克口服剂量的PK数据。此外，相对于同一受试者的一次给药，对单个受试者测试了三个连续剂量的效果，以确定血浆最大浓度（Cmax）和血浆浓度-时间曲线下面积（AUC）值是否与那些相当在动物研究中以及在人类中通过静脉输注可实现的研究。方法通过修改已公开的方法从蛋白中分离血浆RLA。通过将溶解在乙醇中的已知浓度的RLA加标并在磷酸盐缓冲液（PBS）中稀释到每个人的基线血浆中来生成标准曲线，以说明蛋白结合之间的个体差异并防止血浆蛋白变性。血浆RLA含量是通过使用高效液相色谱（电化学/电量分析）（HPLC / ECD）的回收百分比确定的。结果如初步研究所预期，与RLA或rac-LA相比，NaRLA较不易聚合，完全溶于水，并且显示出更高的Cmax和AUC值，并且缩短了达到最大浓度（Tmax）和T1 / 2值的时间。为了显着延长Cmax和AUC，有可能以15分钟为间隔施用三剂600 mg RLA剂量（以NaRLA形式），以达到与缓慢（20分钟）LA输注相似的血浆浓度。这是第一个报告即使在可达到的最高血浆浓度下未结合的RLA仍可忽略不计的研究。与RLA或rac-LA相比，NaRLA不易聚合，完全溶于水，并且显示出显着更高的Cmax和AUC值，并且缩短了达到最大浓度（Tmax）和T1 / 2值的时间。为了显着延长Cmax和AUC，有可能以15分钟为间隔施用三剂600 mg RLA剂量（以NaRLA形式），以达到与缓慢（20分钟）LA输注相似的血浆浓度。这是第一个报告即使在可达到的最高血浆浓度下未结合的RLA仍可忽略不计的研究。与RLA或rac-LA相比，NaRLA不易聚合，完全溶于水，并且显示出显着更高的Cmax和AUC值，并且缩短了达到最大浓度（Tmax）和T1 / 2值的时间。为了显着延长Cmax和AUC，有可能以15分钟为间隔施用三剂600 mg RLA剂量（以NaRLA形式），以达到与缓慢（20分钟）LA输注相似的血浆浓度。这是第一个报告即使在可达到的最高血浆浓度下未结合的RLA仍可忽略不计的研究。可以以15分钟的间隔施用三剂600 mg RLA剂量（以NaRLA的形式）以达到类似于缓慢（20分钟）LA输注的血浆浓度。这是第一个报告即使在可达到的最高血浆浓度下未结合的RLA仍可忽略不计的研究。可以以15分钟的间隔施用三剂600 mg RLA剂量（以NaRLA的形式）以达到类似于缓慢（20分钟）LA输注的血浆浓度。这是第一个报告即使在可达到的最高血浆浓度下未结合的RLA仍可忽略不计的研究。