Effects of melatonin on the pharmacokinetics and amino acid metabolism profile of vigabatrin in rats.

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY Toxicology and applied pharmacology Pub Date : 2025-01-28 DOI:10.1016/j.taap.2025.117247

Qiang Zheng, Song-Lin Xu, Xin-Lin Guo, Chuan-Yu Wang, Meng-Die Ma, Jin-Fang Ge

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Abstract

Objectives: Investigating the effect of melatonin (MLT) on the pharmacokinetics and related neurotransmitter and amino acid metabolism of vigabatrin (VGB) in epileptic rats in vivo.

Methods: 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.

Results: Melatonin significantly alters the pharmacokinetics of VGB, primarily by lengthening the elimination t_1/2, 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.

Conclusions: 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.

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研究目的方法：采用高效液相色谱法检测大鼠胃内给药（50、100、200）mg/kg单独或与褪黑素（20 mg/kg）联合给药后VGB的药代动力学和组织分布。一阶消除的单室模型与一阶估计的非线性混合效应模型相拟合。采用靶向代谢组学测量和分析了单独或联合使用 VGB 的凯尼酸（KA）诱导癫痫大鼠海马中的氨基酸水平：结果：褪黑素明显改变了VGB的药代动力学，主要是延长了消除t1/2、Tmax、MRT和Vz/F，降低了维格巴曲林R（-）对映体（R-VGB）和维格巴曲林S（+）对映体（S-VGB）的Cmax。此外，与 VGB 组相比，15 分钟后 VGB + MLT 组肺部和脾脏中 R-VGB 和 S-VGB 的浓度显著增加。1 小时后，脾脏中的 S-VGB 水平明显升高。4 小时后，海马中的 S-VGB 和前额叶皮层中的 R-VGB 水平明显升高。靶向代谢组学实验结果显示，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）的水平降低，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、精氨酸和苯丙氨酸的水平明显升高。在 VGB 和 VGB + MLT 治疗组中，这些升高的神经递质和氨基酸水平有所下降：结论：MLT 影响了 VGB 在大鼠体内的药代动力学和组织分布，延长了其消除时间并改善了组织分布。结论：MLT 影响了 VGB 大鼠的药代动力学和组织分布，延长了 VGB 的消除时间，改善了组织分布，并有助于 VGB 改善癫痫大鼠海马中神经递质和氨基酸的失衡。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Toxicology and applied pharmacology 医学-毒理学

CiteScore

6.80

自引率

2.60%

发文量

309

审稿时长

32 days

期刊介绍： Toxicology and Applied Pharmacology publishes original scientific research of relevance to animals or humans pertaining to the action of chemicals, drugs, or chemically-defined natural products. Regular articles address mechanistic approaches to physiological, pharmacologic, biochemical, cellular, or molecular understanding of toxicologic/pathologic lesions and to methods used to describe these responses. Safety Science articles address outstanding state-of-the-art preclinical and human translational characterization of drug and chemical safety employing cutting-edge science. Highly significant Regulatory Safety Science articles will also be considered in this category. Papers concerned with alternatives to the use of experimental animals are encouraged. Short articles report on high impact studies of broad interest to readers of TAAP that would benefit from rapid publication. These articles should contain no more than a combined total of four figures and tables. Authors should include in their cover letter the justification for consideration of their manuscript as a short article.