Zheng Qiang, Xu Song-Lin, Guo Xin-Lin, Wang Chuan-Yu, Ma Meng-Die, Ge Jin-Fang
School of Pharmacy, Anhui Medical University, Hefei, Anhui 230032, China; Shaoxing People's Hospital, Shaoxing 312000, China; Anhui Provincial Laboratory of Inflammatory and Immune Disease, Anhui Institute of Innovative Drugs, Hefei, Anhui 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei, Anhui 230032, PR China.
School of Pharmacy, Anhui Medical University, Hefei, Anhui 230032, China; Anhui Provincial Laboratory of Inflammatory and Immune Disease, Anhui Institute of Innovative Drugs, Hefei, Anhui 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei, Anhui 230032, PR China.
Toxicol Appl Pharmacol. 2025 Mar;496:117247. doi: 10.1016/j.taap.2025.117247. Epub 2025 Jan 28.
Investigating the effect of melatonin (MLT) on the pharmacokinetics and related neurotransmitter and amino acid metabolism of vigabatrin (VGB) in epileptic rats in vivo.
High performance liquid chromatography was used to examine the pharmacokinetics and tissue distribution of VGB after intragastric administration dosing (50，100，200) mg/kg singly or in combination with melatonin (20 mg/kg) in rats. The single-compartment model of first-order elimination was fitted with the nonlinear mixed-effect model of first-order estimation. Targeting metabolomics were used to measure and analyze the amino acid levels in the hippocampus of kainic acid (KA)-induced epileptic rats treated with VGB alone or coupled melatonin.
Melatonin significantly alters the pharmacokinetics of VGB, primarily by lengthening the elimination t, Tmax, MRT and Vz/F, and decreasing the Cmax of both vigabatrin R(-) enantiomer (R-VGB) and vigabatrin S(+) enantiomer (S-VGB). Moreover, the concentrations of R-VGB and S-VGB were increased significantly in the lung and spleen of VGB + MLT group at 15 min compared with that of the VGB group. At 1 h, S-VGB levels increased significantly in spleen. At 4 h, the levels of S-VGB in the hippocampus and R-VGB in the prefrontal cortex increased significantly. Results of targeted metabolomics experiment showed that compared with control group, the level of aminobutyric acid/glutamate (GABA/Glu) in hippocampus of KA-induced epileptic rats was decreased, while glutamate/glutamine (Glu/Gln), tyrosine, dopamine, 3-methoxytyramine, tryptophan, 5-hydroxytryptamine, arginine and phenylalanine were significantly increased. These elevated levels of neurotransmitters and amino acids were decreased in VGB- and VGB + MLT treated group.
MLT affected the pharmacokinetics and tissue distribution of VGB in rats, prolonging its elimination time and improving the tissue distribution. Moreover, it might help VGB improve the imbalance of neurotransmitters and amino acids in the hippocampus of epileptic rats.
研究褪黑素（MLT）对癫痫大鼠体内氨己烯酸（VGB）药代动力学及相关神经递质和氨基酸代谢的影响。
采用高效液相色谱法检测大鼠单剂量（50、100、200）mg/kg或与褪黑素（20 mg/kg）联合灌胃给药后VGB的药代动力学和组织分布。采用一级消除单室模型拟合一级估算的非线性混合效应模型。运用靶向代谢组学技术测定和分析单独使用VGB或联合褪黑素治疗的红藻氨酸（KA）诱导的癫痫大鼠海马中的氨基酸水平。
褪黑素显著改变了VGB的药代动力学，主要表现为延长消除t、Tmax、MRT和Vz/F，并降低氨己烯酸R（-）对映体（R-VGB）和氨己烯酸S（+）对映体（S-VGB）的Cmax。此外，与VGB组相比，VGB+MLT组在15分钟时肺和脾中R-VGB和S-VGB的浓度显著升高。在1小时时，脾中S-VGB水平显著升高。在4小时时，海马中S-VGB水平和前额叶皮质中R-VGB水平显著升高。靶向代谢组学实验结果表明，与对照组相比，KA诱导的癫痫大鼠海马中氨基丁酸/谷氨酸（GABA/Glu）水平降低，而谷氨酸/谷氨酰胺（Glu/Gln）、酪氨酸、多巴胺、3-甲氧基酪胺、色氨酸、5-羟色胺、精氨酸和苯丙氨酸显著升高。在VGB和VGB+MLT治疗组中，这些升高的神经递质和氨基酸水平降低。
MLT影响大鼠体内VGB的药代动力学和组织分布，延长其消除时间并改善组织分布。此外，它可能有助于VGB改善癫痫大鼠海马中神经递质和氨基酸的失衡。
