ENANTIOSELECTIVE PHARMACOKINETICS AND BIOAVAILABILITY OF DIFFERENT RACEMIC ALPHA-LIPOIC ACID FORMULATIONS IN HEALTHY-VOLUNTEERS

The pharmacokinetics and the absolute bioavailability of the enantiome rs of alpha-lipoic acid (alpha-LA) from different dosage forms have be en studied for the first time in twelve healthy volunteers using a spe cific enantioselective HPLC assay. Single doses of 200 mg racemic alph a-LA were administered orally (four tablets each containing 50 mg, 200 mg tablet and oral solution) and intravenously (4 min constant rate i nfusion), in random order. The IV infusion resulted in mean peak plasm a levels (C-max) of 13.0 mu g ml(-1) (range 8.45-21.06 mu g ml(-1)) fo r the R(+)- and 11.6 mu g ml(-1) (range 6.40-19.64 mu g ml(-1)) for th e S(-) form (P<0.001). Plasma concentrations of both alpha-LA-enantiom ers declined with mean terminal half lives (t(1/2)) of 0.37+/-0.25 h f or R(+)- and 0.32+/-0.14 h for S(-)-alpha-LA. The areas under the curv e (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)) fo r R(+)- and S(-)-alpha-LA, respectively (P<0.001). The mean total plas ma 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 live r for both enantiomers. The apparent volume of distribution (V-z) of b oth enantiomers, in contrast, was not significantly different from eac h 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 t he 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. H ighest 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(-)-alp ha-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). Th e 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 accordan ce 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, r espectively. In conclusion, the F-abs of the R(+)-enantiomer of alpha- LA was shown to be significantly higher compared to the values which c ould be achieved for S(-)-alpha-LA. This observation was in general ap plicable and independent from the galenical formulations used.