Preclinical tissue distribution and metabolic correlations of vigabatrin, an antiepileptic drug associated with potential use‐limiting visual field defects

Abstract

Vigabatrin (VGB; (S)‐(+)/(R)‐(‐) 4‐aminohex‐5‐enoic acid), an antiepileptic irreversibly inactivating GABA transaminase (GABA‐T), manifests use‐limiting ocular toxicity. Hypothesizing that the active S enantiomer of VGB would preferentially accumulate in eye and visual cortex (VC) as one potential mechanism for ocular toxicity, we infused racemic VGB into mice via subcutaneous minipump at 35, 70, and 140 mg/kg/d (n = 6‐8 animals/dose) for 12 days. VGB enantiomers, total GABA and β‐alanine (BALA), 4‐guanidinobutyrate (4‐GBA), and creatine were quantified by mass spectrometry in eye, brain, liver, prefrontal cortex (PFC), and VC. Plasma VGB concentrations increased linearly by dose (3 ± 0.76 (35 mg/kg/d); 15.1 ± 1.4 (70 mg/kg/d); 34.6 ± 3.2 μmol/L (140 mg/kg/d); mean ± SEM) with an S/R ratio of 0.74 ± 0.02 (n = 14). Steady state S/R ratios (35, 70 mg/kg/d doses) were highest in eye (5.5 ± 0.2; P < 0.0001), followed by VC (3.9 ± 0.4), PFC (3.6 ± 0.3), liver (2.9 ± 0.1), and brain (1.5 ± 0.1; n = 13‐14 each). Total VGB content of eye exceeded that of brain, PFC and VC at all doses. High‐dose VGB diminished endogenous metabolite production, especially in PFC and VC. GABA significantly increased in all tissues (all doses) except brain; BALA increases were confined to liver and VC; and 4‐GBA was prominently increased in brain, PFC and VC (and eye at high dose). Linear correlations between enantiomers and GABA were observed in all tissues, but only in PFC/VC for BALA, 4‐GBA, and creatine. Preferential accumulation of the VGB S isomer in eye and VC may provide new insight into VGB ocular toxicity.

Metabolomic analyses of vigabatrin (VGB)-treated mice: GABA-transaminase inhibition significantly alters amino acid profiles in murine neural and non-neural tissues

“…Preparation and purification of VGB, as well as subcutaneous infusion of VGB to mice, has been recently described (Walters et al 2019). In brief, C57BL/6J mice (Jackson Laboratories, Bar Harbor, ME) were bred in-house to obtain required cohort size (n=6-8 per dose group, male only), and were 8-10 weeks of age and 20.8-26.1 g in weight.…”

“…Animals were randomly assigned to vehicle or drug cohorts. Loading of pumps, surgical implantation, and duration of use (12 days) has been described (Walters et al 2019). Tissues isolated for analysis included intact eye, liver, prefrontal cortex (PFC, including both gray and white matter), visual cortex (VC), the remainder of the intact brain, and plasma.…”

“…Amino acids were quantified by UPLC (Waters UPLC® MassTrak™ Amino Acid Analysis (AAA) Solution) as described (Vogel et al 2017). VGB was quantified by liquid-chromatography tandem mass spectrometry employing 2 H 4 -gabapentin as described (Walters et al 2019). GraphPad Prism (version 8.0; San Diego, CA) was used for data and statistical analyses, the latter using one-way ANOVA with post-hoc analysis and significance set at p<0.05.…”

Vigabatrin-Induced Retinal Functional Alterations and Second-Order Neuron Plasticity in C57BL/6J Mice

“…This VGB dose of 140 mg/kg/d was based on human clinical doses. 2 VGB was synthesized as described in Walters et al, 2019 17 for the first cohort of 12 C57BL/6J mice (n = 6 per treatment group) and purchased from Sigma-Aldrich (St. Louis, MO) for the second and third cohorts of mice (n = 12 per treatment group).…”

“…The tissues were stored at -80°C and shipped on dry ice for extraction and quantification of VGB and GABA concentrations in tissue samples, performed as described by Walters et al. 17…”