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 (F_D→KIC) was estimated by using the area under the curve (AUC) of [²H₇]KIC on thed-[²H₇]leucine administration [AUC_KIC(←D)] and that of [²H₇]KIC on the [²H₇]KIC administration (AUC_KIC) to yield 70.1%. The fraction of conversion from [²H₇]KIC tol-[²H₇]leucine (F_KIC→L) was 40.2%. The fraction of conversion fromd-leucine to the l-enantiomer (F_D→L) was considered to be the product of F_D→KIC and F_KIC→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, F_D→L was also calculated directly using AUC_L(←D) and AUC_L to yield 27.5%. There were no differences between the two F_D→L values, suggesting that almost all of the formation ofl-[²H₇]leucine fromd-[²H₇]leucine occurred via [²H₇]KIC as an intermediate.