Hasegawa Hiroshi, Matsukawa Takehisa, Shinohara Yoshihiko, Hashimoto Takao
Department of Pathophysiology, School of Pharmacy, Tokyo University of Pharmacy and Life Science, Tokyo, Japan.
Drug Metab Dispos. 2002 Dec;30(12):1436-40. doi: 10.1124/dmd.30.12.1436.
D-Leucine is considered to be converted into the L-enantiomer by two steps: oxidative deamination to form alpha-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 the L-enantiomer. After intravenous administrations of D-[(2)H(7)]leucine, L-[(2)H(7)]leucine, or [(2)H(7)]KIC, their plasma concentrations together with endogenous L-leucine and KIC were determined by gas chromatography-mass spectrometry. The rapid appearances of [(2)H(7)]KIC and L-[(2)H(7)]leucine were observed after administration of D-[(2)H(7)]leucine, whereas no detectable amount of D-[(2)H(7)]leucine was found after administrations of [(2)H(7)]KIC or L-[(2)H(7)]leucine. The fraction of conversion from D-[(2)H(7)]leucine into [(2)H(7)]KIC (F(D-->KIC)) was estimated by using the area under the curve (AUC) of [(2)H(7)]KIC on the D-[(2)H(7)]leucine administration [AUC(KIC(D))] and that of [(2)H(7)]KIC on the [(2)H(7)]KIC administration (AUC(KIC)) to yield 70.1%. The fraction of conversion from [(2)H(7)]KIC to L-[(2)H(7)]leucine (F(KIC-->L)) was 40.2%. The fraction of conversion from D-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-[(2)H(7)]leucine was metabolized to L-[(2)H(7)]leucine via [(2)H(7)]KIC. These results suggested that the relatively low conversion of D-leucine into the L-enantiomer might depend on irreversible decarboxylation of KIC. Regardless of [(2)H(7)]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 of L-[(2)H(7)]leucine from D-[(2)H(7)]leucine occurred via [(2)H(7)]KIC as an intermediate.
D-亮氨酸被认为通过两步转化为L-对映体：氧化脱氨形成α-酮异己酸（KIC），随后KIC进行立体特异性再氨基化。我们研究了大鼠体内亮氨酸对映体和KIC的药代动力学，以评估D-亮氨酸的脱氨、KIC的再氨基化以及KIC的脱羧对将D-亮氨酸转化为L-对映体的总体程度的影响。静脉注射D-[(2)H(7)]亮氨酸、L-[(2)H(7)]亮氨酸或[(2)H(7)]KIC后，通过气相色谱-质谱法测定它们的血浆浓度以及内源性L-亮氨酸和KIC的浓度。静脉注射D-[(2)H(7)]亮氨酸后，观察到[(2)H(7)]KIC和L-[(2)H(7)]亮氨酸迅速出现，而静脉注射[(2)H(7)]KIC或L-[(2)H(7)]亮氨酸后未发现可检测到的D-[(2)H(7)]亮氨酸。通过使用静脉注射D-[(2)H(7)]亮氨酸时[(2)H(7)]KIC的曲线下面积（AUC）[AUC(KIC(D))]和静脉注射[(2)H(7)]KIC时[(2)H(7)]KIC的曲线下面积（AUC(KIC)）来估计从D-[(2)H(7)]亮氨酸转化为[(2)H(7)]KIC的转化率（F(D→KIC)），结果为70.1%。从[(2)H(7)]KIC转化为L-[(2)H(�)]亮氨酸的转化率（F(KIC→L)）为40.2%。从D-亮氨酸转化为L-对映体的转化率（F(D→L)）被认为是F(D→KIC)和F(KIC→L)的乘积，这表明28.2%的D-[(2)H(7)]亮氨酸通过[(2)H(7)]KIC代谢为L-[(2)H(7)]亮氨酸。这些结果表明，D-亮氨酸向L-对映体的相对低转化率可能取决于KIC的不可逆脱羧。无论是否存在[(2)H(7)]KIC，也直接使用AUC(L(D))和AUC(L)计算F(D→L)，结果为27.5%。两个F(D→L)值之间没有差异表明，从D-[(2)H(7)]亮氨酸形成L-[(2)H(7)]亮氨酸几乎全部通过[(2)H(7)]KIC作为中间体发生。
