AbstractObjectivesTo investigate the comparative antiseizure activity of the individual enantiomers of fenfluramine and its major active primary metabolite norfenfluramine in rodent seizure models, and its relationship with the pharmacokinetics of these compounds in plasma and brain.MethodsThe antiseizure potency ofd,l‐fenfluramine (racemic fenfluramine) was compared with the respective potencies of its individual enantiomers and the individual enantiomers of norfenfluramine using the maximal electroshock (MES) test in rats and mice, and the 6‐Hz 44 mA test in mice. Minimal motor impairment was assessed simultaneously. The time course of seizure protection in rats was compared with the concentration profiles ofd‐fenfluramine,l‐fenfluramine, and their primary active metabolites in plasma and brain.ResultsAll compounds tested were active against MES‐induced seizures in rats and mice after acute (single‐dose) administration, but no activity against 6‐Hz seizures was found even at doses up to 30 mg/kg. Estimates of median effective doses (ED₅₀) in the rat‐MES test were obtained for all compounds except ford‐norfenfluramine, which caused dose‐limiting neurotoxicity. Racemic fenfluramine had approximately the same antiseizure potency as its individual enantiomers. Bothd‐andl‐fenfluramine were absorbed and distributed rapidly to the brain, suggesting that seizure protection at early time points (≤2 h) was related mainly to the parent compound. Concentrations of all enantiomers in brain tissue were >15‐fold higher than those in plasma.SignificanceAlthough there are differences in antiseizure activity and pharmacokinetics among the enantiomers of fenfluramine and norfenfluramine, all compounds tested are effective in protecting against MES‐induced seizures in rodents. In light of the evidence linking thed‐enantiomers to cardiovascular and metabolic adverse effects, these data suggest thatl‐fenfluramine andl‐norfenfluramine are potentially attractive candidates for a chiral switch approach leading to development of a novel, enantiomerically‐pure antiseizure medication.