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The effect of the anorectic agent, d ‐fenfluramine, and its primary metabolite, d ‐norfenfluramine, on intact human platelet serotonin uptake and efflux
Author(s) -
Johnson G. J.,
Leis L. A.,
Dunlop P. C.,
Weir E. K.
Publication year - 2003
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1046/j.1538-7836.2003.00474.x
Subject(s) - fenfluramine , anorectic , chemistry , pharmacology , serotonin , dexfenfluramine , metabolite , efflux , platelet , endocrinology , medicine , biochemistry , biology , receptor , body weight
Summary. Dexfenfluramine, a drug formerly prescribed for treatment of obesity, caused heart valve damage and pulmonary hypertension in some people. The cause of the toxicity has not been defined, but 5‐HT has been implicated. The objective of this study was to evaluate the effect of the anorectic agent, d ‐fenfluramine, and its major metabolite, d ‐norfenfluramine, on intact human platelet serotonin (5‐HT) transport in vitro. The effects of d ‐fenfluramine and d ‐norfenfluramine on platelet uptake and efflux of 3 H‐5‐HT were measured in buffer at pH 6.7, to optimize serotonin transporter (SERT) function, and at pH 7.4. Uptake of 3 H‐5‐HT at pH 6.7 and 7.4 was inhibited by both agents at µ m concentrations (IC 50 , d ‐fenfluramine approximately 3 µ m ; d ‐norfenfluramine approximately 10 µ m ). However, no efflux of 3 H‐5‐HT from labeled platelets at either pH 6.7 or 7.4 occurred at similar concentrations of d ‐fenfluramine or d ‐norfenfluramine. With inhibition of platelet dense granule 3 H‐5‐HT uptake by reserpine, efflux of 3 H‐5‐HT was observed at pH 6, but not at pH 7.4. Fluoxetine, a SERT inhibitor, was a more potent inhibitor of uptake (IC 50 0.05 µ m ) than d ‐fenfluramine, but the anorectic agent, phentermine, had no effect. Therefore, d ‐fenfluramine and d ‐norfenfluramine inhibit human platelet uptake of 5‐HT in vitro at tissue concentrations attainable in vivo , but they do not stimulate 5‐HT efflux due to dense granule sequestration. Inhibition of platelet 5‐HT uptake may play a role in the cardiopulmonary toxicity of d ‐fenfluramine, but other factors probably contribute, since similar toxicity has not been observed with fluoxetine.