Pharmacokinetics of d- and l-norfenfluramine following their administration as individual enantiomers in rats.

Abstract

The 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 recently reported. To complement these findings, we investigated the pharmacokinetics of d- and l-norfenfluramine in rat plasma and brain samples. Sprague Dawley rats were injected intraperitoneally (i.p.) with 20mg/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 Chromatograph/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.