Drug-Related Brain Vacuolation as an Unusual Presentation of Neurotoxicity in Sprague Dawley Rats

Abstract

In a 4-week rat study, a nucleotide prodrug antiviral agent containing a synthetic non-natural amino acid (C-331) induced a dose-related vacuolation in the brain’s white matter tracts without concurrent neuronal loss, gliosis, or neurological deficits. Routine safety pharmacology studies showed no effects. Penetration of the drug through the blood-brain barrier was negligible. Rat-specific metabolites were not evident. A follow-up 13-week rat study with a 4-week interim assessment was performed using oral doses of 0, 100, 300, or 1000 mg/kg/day for 4 or 13 weeks. Intermittent, transient clonic convulsions (