The effect of the anorectic agent, d-fenfluramine, and its primary metabolite, d-norfenfluramine, on intact human platelet serotonin uptake and efflux.

Abstract

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.

• Authors: G J Johnson, L A Leis, P C Dunlop, E K Weir
• Journal: Journal of thrombosis and haemostasis : JTH (J Thromb Haemost) Vol. 1 Issue 12 Pg. 2663-8 (Dec 2003) ISSN: 1538-7933 [Print] England
• PMID: 14675103 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Appetite Depressants
• Serotonin Uptake Inhibitors
• Fluoxetine
• Norfenfluramine
• Fenfluramine
• Serotonin
• Reserpine
• Phentermine

Topics

• Appetite Depressants (pharmacology)
• Blood Platelets (drug effects, metabolism)
• Dose-Response Relationship, Drug
• Fenfluramine (pharmacology)
• Fluoxetine (pharmacology)
• Humans
• Hydrogen-Ion Concentration
• Norfenfluramine (pharmacology)
• Phentermine (pharmacology)
• Reserpine (pharmacology)
• Secretory Vesicles
• Serotonin (metabolism)
• Selective Serotonin Reuptake Inhibitors (pharmacology)