Pharmacokinetics and tissue distribution of vigabatrin enantiomers in rats

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.

Fig. 1

Chromatograms of analytes recorded in HPLC from rat plasma, eye and hippocampal homogenates. a: blank plasma sample; b: blank plasma sample spiked with IS and VGB; c: blank eye sample; d: blank eye sample spiked with IS and VGB; e: blank hippocampus sample; f: blank hippocampus sample spiked with IS and VGB; VGB: Vigabatrin; 1:IS(L-high arginine hydrochloride); 2: R(-) enantiomer in VGB; 3: S(+) enantiomer in VGB.

Fig. 2

Plasma concentration–time curves after the intragastric administration of VGB racemate ang its single enantiomers a: VGB racemate (200 mg/kg) was gavaged in rats; b: VGB racemate (100 mg/kg) was gavaged in rats; c: VGB racemate (50 mg/kg) was gavaged in rats; d: single enantiomer R-VGB(200 mg/kg) and S-VGB(200 mg/kg) were gavaged separately in rats; e: single enantiomer R-VGB(100 mg/kg) and S-VGB(100 mg/kg) were gavaged separately in rats; f: single enantiomer R-VGB(50 mg/kg) and S-VGB(50 mg/kg) were gavaged separately in rats. Data are expressed as mean ± SD, n = 6.

Fig. 3

Dynamic distribution of VGB racemate (200 mg/kg) in different tissues in rats a-h indicate the differences in the contents of S-VGB and R-VGB in the eye, hippocampus, prefrontal cortex, heart, liver, spleen, lungs and kidneys, respectively, at different times after VGB racemate（200 mg/kg）gavage in rats. Data are expressed as mean ± SD, n = 6. *P＜0.05, **P＜0.01 compared with R-VGB.

Fig. 4

Dynamic distribution of single enantiomer R-VGB (200 mg/kg) and S-VGB (200 mg kg) in different tissues in rats a-h indicate the differences in the contents of S-VGB and R-VGB in the eye, hippocampus, prefrontal cortex, heart, liver, spleen, lungs and kidneys, respectively, at different times after single enantiomer R-VGB (200 mg/kg) and S-VGB (200 mg kg) gavage in rats. Data are expressed as mean ± SD, n = 6. *P＜0.05, **P＜0.01 compared with R-VGB.