Kinetics of fenfluramine isomers in the rat

Abstract

The kinetics of fenfluramine isomers were studied in the rat following oral doses of racemic fenfluramine. The data, analyzed using an analogue computer, indicate that the d-fenfluramine is metabolised and excreted at a slower rate than the 1-isomer, resulting in higher plasma and brain concentrations. The kinetic parameters of both isomers were dose-dependent. The rates of disappearance decreased as the dose was raised. The increase in brain area under the curves (AUC) was much greater than the increase of the dose. These findings suggested the rat has a limited capacity for disposition of fenfluramine.

Comparative activity of the enantiomers of fenfluramine and norfenfluramine in rodent seizure models, and relationship with their concentrations in plasma and brain

“…7,14 The pharmacokinetic profiles of fenfluramine enantiomers in the plasma and brain tissue of rats were comparable with those described in earlier reports. [25][26][27][28][29] A comparison of the pharmacokinetic profiles with the time course of antiseizure effects provides interesting clues in understanding the relative contribution of different enantiomers to protection against MES-induced seizures in rats. After administration fenfluramine and its individual enantiomers, the onset of antiseizure activity was rapid (.25 h for d,l-fenfluramine and l-fenfluramine, and 2 h for d-fenfluramine), and the brain concentrations of the formed active metabolites d-and, especially, l-norfenfluramine at these early time points were much lower than those of their respective parent compound.…”

“…Accordingly, the sustained antiseizure activity of l-fenfluramine at 4 h was probably due primarily to its metabolite l-norfenfluramine, whose brain concentration at that time was much higher than that of the parent compound. Because the pharmacokinetic profiles of fenfluramine's individual enantiomers remain unchanged irrespective of whether individual enantiomers or their racemic mixture are administered, 27,[29][30][31] the same considerations can also be applied to interpret the relative contribution of different enantiomers after administration of the racemic drug. A limitation of our study is that pharmacokinetic and pharmacodynamic studies were conducted in different sets of rats.…”

“…14 In rats and mice, l-fenfluramine has a very short half-life due to its rapid biotransformation to l-norfenfluramine. 27 This concern, however, does not apply to humans, in whom lfenfluramine has a much longer half-life (18-25 h) 27,30,32 and represents the most abundant active entity found in the circulation during chronic dosing with fenfluramine. 30 One potential advantage of l-norfenfluramine over l-fenfluramine, on the other hand, is its longer halflife in humans (33-50 h) 27,30 and its lower susceptibility to drug interactions caused by concomitant medications.…”

Importance of establishing the presence of drug active metabolites

“…6). For reasons of kinetics at shorter time periods, the presence of dF predominates in the brain while at longer time periods there is more dNF (14). Both compounds are anorectic, dNF being slightly more effective than dF (15).…”

Differences Between d‐Fenfluramine and d‐Norfenfluramine in Serotonin Presynaptic Mechanisms

“…d-Fenfluramine (d-F) and its active metabolite dnorfenfluramine (d-NF) act mainly by releasing serotonin from nerve terminals and inhibiting its reuptake (Garattini et al, 1978;1979;Mennini et al, 1981a), although they differ markedly in their in vitro mechanisms of action and their in vivo pharmacokinetics (Caccia et al, 1981;Mennini et al, 1982). The aim of the present study was to obtain more complete information on the intimate mechanism by which d-F and d-NF act on serotonin (5-HT) uptake.…”