The effect of the anorectic agent, d-fenfluramine, and its primary metabolite, d-norfenfluramine, on intact human platelet serotonin uptake and efflux.
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 3H-5-HT were measured in buffer at pH 6.7, to optimize serotonin transporter (SERT) function, and at pH 7.4. Uptake of 3H-5-HT at pH 6.7 and 7.4 was inhibited by both agents at micro m concentrations (IC50, d-fenfluramine approximately 3 microM; d-norfenfluramine approximately 10 microM). However, no efflux of 3H-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 3H-5-HT uptake by reserpine, efflux of 3H-5-HT was observed at pH 6, but not at pH 7.4. Fluoxetine, a SERT inhibitor, was a more potent inhibitor of uptake (IC50 0.05 microM) 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.
Johnson
G J
GJ
Hematology/Oncology Section, Medical Service, Minneapolis Veterans Affairs Medical Center, and Department of Medicine, University of Minnesota, Minneapolis, 55417, USA. johns337@umn.edu
Leis
L A
LA
Dunlop
P C
PC
Weir
E K
EK
D001067:Appetite Depressants / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005277:Fenfluramine / Q000494:pharmacology*; D005473:Fluoxetine / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D009642:Norfenfluramine / Q000494:pharmacology*; D010645:Phentermine / Q000494:pharmacology; D012110:Reserpine / Q000494:pharmacology; D022142:Secretory Vesicles; D012701:Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology
D001067:Appetite Depressants; D005277:Fenfluramine; D005473:Fluoxetine; D009642:Norfenfluramine; D010645:Phentermine; D012110:Reserpine; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors