ABSTRACT
Vigabatrin (VGB) (gamma-vinyl-GABA) was rationally designed to be a selective, enzyme-activated, irreversible inhibitor of GABA-transaminase (GABA-T), the enzyme catalyzing the breakdown of GABA. VGB substitutes for GABA, the natural substrate of this enzyme and, once accepted into the enzyme’s active site, is converted by the enzyme’s normal catalytic action to a reactive species which irreversibly inactivates the enzyme’s ability to catabolize subsequent GABA molecules. Chronic oral administration of VGB to rodents and dogs produces histopathologic changes limited to the brain and consisting of microvacuoles in selected white matter tracts without evidence or demyelinization. In view of the findings in animal toxicologic studies, special emphasis has been placed on monitoring the safety of VGB treatment. VGB is currently marketed in the United Kingdom and the Republic of Ireland, is approved for marketing in France and Sweden, and marketing applications have been filed in 10 additional countries.
