Pharmacokinetics and tissue distribution of vigabatrin enantiomers in rats

Qiang Zheng; Shuai He; Song-Lin Xu; Meng-Die Ma; Min Fan; Jin-Fang Ge

doi:10.1016/j.jsps.2023.101934

Pharmacokinetics and tissue distribution of vigabatrin enantiomers in rats

Saudi Pharm J. 2024 Feb;32(2):101934. doi: 10.1016/j.jsps.2023.101934. Epub 2023 Dec 23.

Authors

Qiang Zheng^{1

2

3}, Shuai He^{1

2

3}, Song-Lin Xu^{1

2

3}, Meng-Die Ma^{1

2

3}, Min Fan^{1

2

3}, Jin-Fang Ge^{1

2

3}

Affiliations

¹ School of Pharmacy, Anhui Medical University, Hefei, Anhui 230032, PR China.
² Anhui Provincial Laboratory of Inflammatory and Immune Disease, Anhui Institute of Innovative Drugs, Hefei, Anhui 230032, PR China.
³ The Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei, Anhui 230032, PR China.

Abstract

Purpose: To investigate the pharmacokinetics and tissue distribution of VGB racemate and its single enantiomers, and explore the potential of clinic development for single enantiomer S-VGB.

Methods: In the pharmacokinetics study, male Sprague-Dawley rats were gavaged with VGB racemate or its single enantiomers dosing 50, 100 or 200 mg/kg, and the blood samples were collected during 12 h at regular intervals. In the experiment of tissue distribution, VGB and its single enantiomers were administered intravenously dosing 200 mg/kg, and the tissues including heart, liver, spleen, lung and kidney, eyes, hippocampus, and prefrontal cortex were separated at different times. The concentrations of R-VGB and S-VGB in the plasma and tissues were measured using HPLC.

Results: Both S-VGB and R-VGB could be detected in the plasma of rats administered with VGB racemate, reaching Cmax at approximately 0.5 h with t_1/2 2-3 h. There was no significant pharmacokinetic difference between the two enantiomers when VGB racemate was given 200 mg/kg and 100 mg/kg. However, when given at the dose of 50 mg/kg, S-VGB presented a shorter t_1/2 and a higher Cl/F than R-VGB, indicating a faster metabolism of S-VGB. Furthermore, when single enantiomer was administered respectively, S-VGB presented a slower metabolism than R-VGB, as indicated by a longer t_1/2 and MRT but a lower Cmax. Moreover, compared with the VGB racemate, the single enantiomers S-VGB and R-VGB had shorter t_1/2 and MRT, higher Cmax and AUC/D, and lower Vz/F and Cl/F, indicating the stronger oral absorption and faster metabolism of single enantiomer. In addition, regardless of VGB racemate administration or single enantiomer administration, S-VGB and R-VGB had similar characteristics in tissue distribution, and the content of S-VGB in hippocampus, prefrontal cortex and liver was much higher than that of R-VGB.

Conclusions: Although there is no transformation between S-VGB and R-VGB in vivo, those two enantiomers display certain disparities in the pharmacokinetics and tissue distribution, and interact with each other. These findings might be a possible interpretation for the pharmacological and toxic effects of VGB and a potential direction for the development and optimization of the single enantiomer S-VGB.

Keywords: Distribution; Pharmacokinetics; Single enantiomer; Vigabatrin.