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

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, 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.