Effect of Fenfluramine on 5‐hydroxytryptamine Uptake and Release by Rat Blood Platelets

Abstract

(+)‐Fenfluramine reduces the central stores of 5‐hydroxytryptamine (5‐HT) by a poorly understood mechanism. Rat blood platelets have been used in this study as a simple model for serotoninergic nerve endings. (+)‐Fenfluramine shows a dual effect: it inhibits the uptake of [14C]‐5‐HT by platelets and it releases newly absorbed [14C]‐5‐HT from platelets. The inhibition of [14C]‐5‐HT uptake induced by (+)‐fenfluramine appears very rapidly, is concentration‐dependent and seems not to be competitive. (+)‐Fenfluramine is ten times less effective than chloroimipramine but ten times more effective than (+)‐amphetamine; (+)‐fenfluramine is more active than its (‐)‐isomer or its metabolite norfenfluramine ((+)‐ or (‐)‐form). The release of [14C]‐5‐HT from platelets induced by (+)‐fenfluramine is concentration‐dependent but increases with increased incubation time. Both chloroimipramine and (+)‐amphetamine are in comparison very poor release inducers; (+)‐fenfluramine is more active than its (‐)‐isomer or its metabolites. The effect on [14C]‐5‐HT uptake exerted by (+)‐fenfluramine and chloroimipramine in vitro could not be observed in vivo. The observed effect of fenfluramine on the uptake and release of 5‐HT may explain the lowering action of fenfluramine on the brain 5‐HT level, an effect considered of importance for the anorectic effect of this drug.

Additive effects on rat brain 5HT release of combining phentermine with dexfenfluramine

“…10 The potent 5HT-releasing action of fenfluramines noted in the hypothalamus (Gundlah et al 5 and present data), the striatum 16 and in the nucleus accumbens 13,15 has also been demonstrated using blood platelets. 22,23 This could provide a peripheral source of 5HT that is sufficient to play a role in the genesis of valvulopathy. Alternatively, the cellular accumulation of fenfluramine with or without phentermine 14 or direct 5HT receptor stimulation by a fenfluramine metabolite 11 or otherwise could trigger events that lead to valvulopathy.…”

MDMA (Ecstasy) Inhibition of MAO Type A and Type B: Comparisons with Fenfluramine and Fluoxetine (Prozac)

“…Both drugs bind to the sero tonin transporter, with a similar affinity (Poblete et al 1989). MDMA and FEN both release serotonin (E.C.so = 2.92 and 7.90 IlmollL, respectively, Berger et al 1992;Borroni et al 1983;Buczko et al 1975;Johnson et al 1986;Kannengiesser et al 1976;Schmidt et al 1987), with FEN being more potent. In contrast, MDMA ap pears to be slightly more potent than FEN at inhibition of reuptake (0.42 IlmollL, Steele et al 1987 and0.876 IlmollL, Borroni et al 1983, respectively).…”

Monoamine oxidase inhibition is unlikely to be relevant to the risks associated with phentermine and fenfluramine: a comparison with their abilities to evoke monoamine release

“…The acute ability of S( þ )-fenfluramine and its active metabolite to release 5HT from blood platelets 25,26 could provide a peripheral source of 5HT that is relevant to the pathobiology. However, plasma 5HT changes after drug treatment are difficult to interpret since it is very likely that repeated fenfluramine treatment will deplete platelets of their 5HT stores 27 and may even cause plasma 5HT levels to fall, as demonstrated both in rats given S( þ )-fenfluramine for 14 days 27 and in patients treated with fenfluramine and phentermine for at least 2 months.…”