Revised Pharmacokinetic Constants for Use under Système International

1988 ◽  
Vol 11 (6) ◽  
pp. 338-346
Author(s):  
Robert G. Peterson
Keyword(s):  
Pharmacokinetic Constants

Determination of pharmacokinetic constants after multiple infusions of drugs

1982 ◽  
Vol 23 (4) ◽  
pp. 353-358 ◽  
Author(s):  
L. E. Mather ◽  
R. L. Ringrose ◽  
K. L. Austin
Keyword(s):  
Pharmacokinetic Constants

scholarly journals Unexpected differences in the pharmacokinetics of N-acetyl-DL-leucine enantiomers after oral dosing and their clinical relevance

2019 ◽  
Author(s):  
Grant C. Churchill ◽  
Michael Strupp ◽  
Antony Galione ◽  
Frances M. Platt
Keyword(s):  
Chronic Administration ◽  
The Body ◽  
Maximum Plasma ◽  
Negative Effects ◽  
Chiral Drugs ◽  
Time Curve ◽  
Tissue Samples ◽  
Pharmacologically Active ◽  
Pharmacokinetic Constants ◽  
Noncompartmental Model

AbstractThese results suggest that during chronic administration of the racemate, the D-enantiomer would accumulate, which could have negative effects. 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). 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 isolated N-acetyl-L-leucine.

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