Kinetics of Sequential Metabolism from d-Leucine tol-Leucine via α-Ketoisocaproic Acid in Rat

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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.

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