Abstract
The stereoselective pharmacokinetics of leucine enantiomers in rats has been investigated to evaluate the inversion ofd-leucine to l-enantiomer. After a bolus i.v. administration of d- orl-[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 (+)-α-methoxy-α-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- andl-[2H7]leucine declined biexponentially, with elimination half-lives of 60 and 14 min, respectively. In contrast to the l-enantiomer, thed-enantiomer had a lower systemic clearance. Whend-[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- tod-enantiomer. This methodology has made it possible to evaluate the pharmacokinetics of each enantiomer of amino acids and estimate of chiral inversion after administration ofd-amino acids.
Footnotes
-
Send reprint requests to: Hiroshi Hasegawa, Ph.D., School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan. E-mail:hasegawa{at}ps.toyaku.ac.jp
- Abbreviations used are::
- BCAA
- branched chain amino acid
- GC-MS
- gas chromatography-mass spectrometry
- (+)-MTPA-Cl
- (+)-α-methoxy-α-trifluoromethylphenylacetyl chloride
- SIM
- selected-ion monitoring
- AUC
- area under the plasma concentration-time curve
- AUMC
- area under the first-moment time curve
- MRT
- mean residence time
- CLtot
- total plasma clearance
- Vdss
- volume of distribution at steady state
- KIC
- α-ketoisocaproate
- Received December 20, 1999.
- Accepted May 2, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|