Preclinical tissue distribution and metabolic correlations of vigabatrin, an antiepileptic drug associated with potential use‐limiting visual field defects. Issue 1 (7th January 2019)

• Record Type: Journal Article
• Authors: Walters, Dana C.; Jansen, Erwin E. W.; Ainslie, Garrett R.; Salomons, Gajja S.; Brown, Madalyn N.; Schmidt, Michelle A.; Roullet, Jean‐Baptiste; Gibson, K. M.
• Is Part Of: Pharmacology research & perspectives. Volume 7:Issue 1(2019)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2019-01-07
• Subjects: β‐alanine -- 4‐guanidinobutyrate -- enantiomers -- GABA -- tissue distribution -- Vigabatrin; Pharmacology -- Periodicals; Drug development -- Periodicals; 615.105
• DOI: 10.1002/prp2.456
• Languages: English
• ISSNs: 2052-1707

Abstract

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.