Abstract
d-Leucine is considered to be converted into thel-enantiomer by two steps: oxidative deamination to form α-ketoisocaproic acid (KIC) and subsequent stereospecific reamination of KIC. We investigated the pharmacokinetics of leucine enantiomers and KIC in rats to evaluate how deamination of d-leucine, reamination of KIC, and decarboxylation of KIC were affected to the overall extent that converted d-leucine into thel-enantiomer. After intravenous administrations ofd-[2H7]leucine,l-[2H7]leucine, or [2H7]KIC, their plasma concentrations together with endogenous l-leucine and KIC were determined by gas chromatography-mass spectrometry. The rapid appearances of [2H7]KIC andl-[2H7]leucine were observed after administration ofd-[2H7]leucine, whereas no detectable amount ofd-[2H7]leucine was found after administrations of [2H7]KIC orl-[2H7]leucine. The fraction of conversion from d-[2H7]leucine into [2H7]KIC (FD→KIC) was estimated by using the area under the curve (AUC) of [2H7]KIC on thed-[2H7]leucine administration [AUCKIC(←D)] and that of [2H7]KIC on the [2H7]KIC administration (AUCKIC) to yield 70.1%. The fraction of conversion from [2H7]KIC tol-[2H7]leucine (FKIC→L) was 40.2%. The fraction of conversion fromd-leucine to the l-enantiomer (FD→L) was considered to be the product of FD→KIC and FKIC→L, indicating that 28.2% of d-[2H7]leucine was metabolized to l-[2H7]leucine via [2H7]KIC. These results suggested that the relatively low conversion of d-leucine into thel-enantiomer might depend on irreversible decarboxylation of KIC. Regardless of [2H7]KIC, FD→L was also calculated directly using AUCL(←D) and AUCL to yield 27.5%. There were no differences between the two FD→L values, suggesting that almost all of the formation ofl-[2H7]leucine fromd-[2H7]leucine occurred via [2H7]KIC as an intermediate.
Footnotes
-
This work was supported in part by grants from the Japan Private School Promotion Foundation and the Science Research Promotion Fund, The Promotion and Mutual Aid Corporation for Private Schools of Japan.
- Abbreviations used are::
- GC-MS
- gas chromatography-mass spectrometry
- KIC
- α-ketoisocaproic acid
- SIM
- selected ion monitoring
- FA→B
- fraction of conversion from compound A to metabolite B
- CL
- clearance
- AUCB(←A)
- AUC of metabolite B formed from compound A
- Received July 29, 2002.
- Accepted September 9, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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Kinetics of Sequential Metabolism from d-Leucine tol-Leucine via α-Ketoisocaproic Acid in Rat
