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

Abstract

((S)-(+)/(R)-(-)) vigabatrin (Sabril^R; 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.

Keywords: 2-aminoadipic acid; GABA; Isomers; Retina; Vigabatrin.

Fig. 1.. Concentration of selected amino acids in retina (R), eye (E), brain (B) and plasma (P) as a function of VGB dose (40 mg/kg/d, 80 mg/kg/d).

Note that taurine represents a sulfonic amino acid, and like 2-aminoadipic acid and ornithine (a component of the urea cycle), is not found in proteins. Statistical analysis employed a one way ANOVA in each tissue with Tukey post-hoc analysis (*p<0.05; **p<0.01; ****p<0.0001). ND, not detected.

Fig. 2.. Ratio of amino acids in retina/eye under untreated (vehicle) conditions.

Standard three letter abbreviations are employed for amino acids. A ratio is not shown for those amino acids that were not detected in either compartment. Additional abbreviations: tau, taurine; PEA, phosphoethanolamine. Note the differential y-axis scale for the GABA ratio (red arrow).

Fig. 3.. Total racemic VGB (A), S-(+)/R-(−) ratio (B) and tissue pools (C) for animals dosed with 0, 40 and 80 mg/kg/d VGB.

Abbreviations: E, eye (minus retina); R, retina; B, brain; P, plasma. Statistical analysis, one-way ANOVA with Tukey post-hoc analysis (**p<0.01; ***p<0.001; ****p<0.0001; ns, not significant).