Preferential accumulation of the active S-(+) isomer in murine retina highlights novel mechanisms of vigabatrin-associated retinal toxicity

Dana C. Walters, Erwin E. W. Jansen, Gajja S. Salomons, Erland Arning, Paula Ashcraft, Teodoro Bottiglieri, Jean-Baptiste Roullet, K. Michael Gibson*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

((S)-(+)/(R)-(-)) vigabatrin (SabrilR; γ-vinyl GABA), an antiepileptic irreversibly inactivating GABA-transaminase, was administered to male C57Bl6 J mice via continuous infusion (0, 40, 80 mg/kg/d) for 12 days. Our study design pooled retina, eye (minus retina), whole brain and plasma from n = 24 animals for each dose to provide n = 8 triplicates per treatment group. Hypothesizing that (S)-(+) VGB (active isomer) would preferentially accumulate in retina, we determined VGB isomers, comprehensive amino acids, and pharmacokinetic parameters. In brain, eye and plasma, the ((S)-(+)/(R)-(-)) ratio varied from 0.73 to 1.29 and 13.3 in retina, accompanied by a partition coefficient (tissue/plasma, ((S)-(+);(R)-(-))) of 5.8;0.34, 0.63;0.49, and 0.51;0.34 in retina, eye and brain, respectively. Racemic VGB (nmol/g; plasma, nmol/mL, range of means for dose) content was: retina, 25–36; eye (minus retina), 4.8–8.0; brain, 3.1–6.8 and plasma, 8.7−14.9. GABA tissue content (nmol/g) was 1246–3335, 18–64 and 2615–3200 as a function of VGB dose for retina, eye (minus retina) and brain, respectively. The retinal glial cell toxin 2-aminoadipic acid also increased with VGB dose (76−96 nmol/g). Partitioning of active (S)-(+) VGB to retina suggests the involvement of a stereospecific transporter, the identification of which could reveal new therapeutic paradigms that might mitigate VGB's well-known retinal toxicity and expand its clinical utility.
Original languageEnglish
Article number106536
JournalEpilepsy Research
Volume170
DOIs
Publication statusPublished - 1 Feb 2021

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