AbstractThe effect of fenfluramine and norfenfluramine enantiomers in rodent seizure models and their correlation with the pharmacokinetics of d‐ and l‐fenfluramine in rats have been reported recently. To complement these findings, we investigated the pharmacokinetics of d‐ and l‐ norfenfluramine in rat plasma and brain. Sprague‐Dawley rats were injected intraperitoneally with 20 mg/kg and 1 mg/kg l‐ norfenfluramine. A 1 mg/kg dose of d‐norfenfluramine was used because higher doses caused severe toxicity. The concentration of each enantiomer in plasma and brain was determined at different time points by liquid chromatography/mass spectrometry. Pharmacokinetic parameters were compared between norfenfluramine enantiomers, and with those reported previously for fenfluramine enantiomers after a 20 mg/kg, i.p., dose. All enantiomers were absorbed rapidly and eliminated, with half‐lives ranging from 0.9 h (l‐fenfluramine) to 6.1 h (l‐ norfenfluramine, 20 mg/kg) in plasma, and from 3.6 h (d‐fenfluramine) to 8.0 h (l‐fenfluramine) in brain. Brain‐to‐plasma concentration ratios ranged from 15.4 (d‐fenfluramine) to 27.6 (d‐norfenfluramine), indicating extensive brain penetration. The fraction of d‐ and l‐fenfluramine metabolized to norfenfluramine was estimated to be close to unity. This work is part of ongoing investigations to determine the potential value of developing enantiomerically pure l‐fenfluramine or l‐norfenfluramine as follow‐up compounds to the marketed racemic fenfluramine.