Assessment of the metabolic chiral inversion of D-leucine in rat by gas chromatography-mass spectrometry combined with a stable isotope dilution analysis.
نویسندگان
چکیده
The stereoselective pharmacokinetics of leucine enantiomers in rats has been investigated to evaluate the inversion of D-leucine to L-enantiomer. After a bolus i.v. administration of D- or L-[2H7]leucine to rats, blood samples were obtained over 6 h after administration and analyzed by a stereoselective gas chromatography-mass spectrometry method. Racemic [2H3]leucine was used as an internal standard. The method involved methyl esterification and subsequent chiral derivatization with (+)-alpha-methoxy-alpha-trifluoromethylphenylacetyl chloride to form the diastereomeric amide. The derivatization made possible the separation of leucine enantiomers with good gas chromatographic behavior. Plasma concentration of both D- and L-[2H7]leucine declined biexponentially, with elimination half-lives of 60 and 14 min, respectively. In contrast to the L-enantiomer, the D-enantiomer had a lower systemic clearance. When D-[2H7]leucine was administered, the L-enantiomer was found to rapidly appear in plasma. About 30% of an administered dose of the D-isomer was stereospecifically inverted to the L-enantiomer. There was no measurable inversion of the L- to D-enantiomer. This methodology has made it possible to evaluate the pharmacokinetics of each enantiomer of amino acids and estimate of chiral inversion after administration of D-amino acids.
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ورودعنوان ژورنال:
- Drug metabolism and disposition: the biological fate of chemicals
دوره 28 8 شماره
صفحات -
تاریخ انتشار 2000