Enantioselective pharmacokinetics and bioavailability of different racemic alpha-lipoic acid formulations in healthy volunteers

The pharmacokinetics and the absolute bioavailability of the enantiomers of alpha-lipoic acid (alpha-LA) from different dosage forms have been studied for the first time in twelve healthy volunteers using a specific enantioselective HPLC assay. Single doses of 200 mg racemic alpha-LA were administered orally (four tablets each containing 50 mg, 200 mg tablet and oral solution) and intravenously (4 min constant rate infusion), in random order. The IV infusion resulted in mean peak plasma levels (C-max) of 13.0 mu g ml(-1) (range 8.45-21.06 mu g ml(-1)) for the R(+)- and 11.6 mu g ml(-1) (range 6.40-19.64 mu g ml(-1)) for the S(-) form (P<0.001). Plasma concentrations of both alpha-LA-enantiomers declined with mean terminal half lives (t(1/2)) of 0.37+/-0.25 h for R(+)- and 0.32+/-0.14 h for S(-)-alpha-LA. The areas under the curve (AUC) calculated were 1.82 mu g . h ml(-1) (range 1.20-2.66 mu g . h ml(-1)) and 1.44 mu g . h ml(-1) (range 0.83-2.16 mu g . h ml(-1)) for R(+)- and S(-)-alpha-LA, respectively (P<0.001). The mean total plasma clearance of 12.24+/-2.62 ml min(-1) kg(-1) for R(+)- and 15.64+/-4.18 ml min(-1) kg(-1) for S(-)-alpha-LA differed also significantly (P<0.001), but was closely related to the normal plasma flow of the liver for both enantiomers. The apparent volume of distribution (V-z) of both enantiomers, in contrast, was not significantly different from each other (R(+)-: 419+/-369 ml kg(-1); S(-)-: 471 +/- 338 ml kg(-1); P = 0.424). After oral dosage C-max was observed at 0.21 +/- 0.07 h for the oral solution (OS), at 0.70 +/- 0.41 h for the 50 mg tablet and at 0.90 +/- 0.74 h for the 200 mg tablet formulation, with apparently no differences between the enantiomers within each formulation. The t(1/2) for all oral dosage forms was comparable to the IV administration. Highest C-max values were observed for the OS with 1.95 mu g ml(-1) for R(+)- (range 0.87-4.76 mu g ml(-1)) and 1.17 mu g ml(-1) for S(-)-alpha-LA (range 0.52-2.76 mu g ml(-1); P<0.001). The AUC of the OS showed similar differences between both enantiomers with 0.65 mu g . h ml(-1) for the R(+)- (range 0.36-1.15 mu g . h ml(-1)) and 0.37 mu g . h ml(-1) (range 0.20-0.64 mu g . h ml(-1)) for the S(-)-form (P<0.001). The absolute bioavailability (F-abs) of the enantiomers from the OS was calculated to be 38 +/- 15 and 28 +/- 14% for R(+)- and S(-)-alpha-LA, respectively (P<0.001). The results of both tablet forms with respect to the pharmacokinetic behaviour of both enantiomers were in accordance with the results of the OS. From both solid dosage forms F-abs was calculated to be about 25 and 20% for the R(+)- and S(-)-enantiomer, respectively. In conclusion, the F-abs of the R(+)-enantiomer of alpha-LA was shown to be significantly higher compared to the values which could be achieved for S(-)-alpha-LA. This observation was in general applicable and independent from the galenical formulations used.