Abstract
The enantiomers of many chiral drugs not only exhibit different pharmacological effects in regard to targets that dictate therapeutic and toxic effects, but are also handled differently in the body due to pharmacokinetic effects. We investigated the pharmacokinetics of the enantiomers of N-acetyl-leucine after administration of the racemate (N-acetyl-DL-leucine) or purified, pharmacologically active L-enantiomer (N-acetyl-L-leucine). The results suggest that during chronic administration of the racemate, the D-enantiomer would accumulate, which could have negative effects. Compounds were administered orally to mice. Plasma and tissue samples were collected at predetermined time points (0.25 to 8 h), quantified with liquid chromatography/mass spectrometry, and pharmacokinetic constants were calculated using a noncompartmental model. When administered as the racemate, both the maximum plasma concentration (Cmax) and the area under the plasma drug concentration over time curve (AUC) were much greater for the D-enantiomer relative to the L-enantiomer. When administered as the L-enantiomer, the dose proportionality was greater than unity compared to the racemate, suggesting saturable processes affecting uptake and/or metabolism. Elimination (ke and T1/2) was similar for both enantiomers. These results are most readily explained by inhibition of uptake at an intestinal carrier of the L-enantiomer by the D-enantiomer, and by first-pass metabolism of the L-, but not D-enantiomer, likely by deacetylation. In brain and muscle, N-acetyl-L-leucine levels were lower than N-acetyl-D-leucine, consistent with rapid conversion into L-leucine and utilization by normal leucine metabolism. In summary, the enantiomers of N-acetyl-leucine exhibit large, unexpected differences in pharmacokinetics due to both unique handling and/or inhibition of uptake and metabolism of the L-enantiomer by the D-enantiomer. Taken together, these results have clinical implications supporting the use of N-acetyl-L-leucine instead of the racemate or N-acetyl-D-leucine, and support the research and development of only N-acetyl-L-leucine.
Highlights
N-acetyl-leucine has been used as an over-the-counter drug for the treatment of vertigo since 1957 [1]
We investigated the pharmacokinetics of the enantiomers of N-acetyl-leucine after administration of the racemate (N-acetyl-DL-leucine) or purified, pharmacologically active L-enantiomer (N-acetyl-L-leucine)
With the above as background regarding safety and efficacy of racemic drugs, and the fact that no data has been published on the pharmacokinetics of the enantiomers of N-acetyl-leucine, we investigated the pharmacokinetics of the racemate as well as the pharmacologically active L-enantiomer alone
Summary
N-acetyl-leucine has been used as an over-the-counter drug for the treatment of vertigo since 1957 [1]. Several mechanisms of action have been suggested including physicochemical partitioning into the phopspholipid bilayer to decrease its fluidity [1], direct action on glycine recptors and AMPA receptors [1], effects on branched chain aminotransferaes affecting glutamate neurotransmission [3], and an increase in glucose metabolism [3]. All of these mechanisms could contrribute to the observed effect of norrmalizing membrane potential and excitability leading to activation of the vestibulocerebellum and a deactivation of the posterolateral thalamus [2,3,5]. Given the broad therapeutic potential of N-acetyl-leucine, its pharmacodynamics and pharmacokinetics warrant further exploration
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