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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.
J Thromb Haemost. 2003 Dec; 1(12):2663-8.JT

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+Show Affiliations

Hematology/Oncology Section, Medical Service, Minneapolis Veterans Affairs Medical Center, and Department of Medicine, University of Minnesota, Minneapolis, 55417, USA. johns337@umn.eduNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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.

Language

eng

PubMed ID

14675103

Citation

Johnson, G J., et al. "The Effect of the Anorectic Agent, D-fenfluramine, and Its Primary Metabolite, D-norfenfluramine, On Intact Human Platelet Serotonin Uptake and Efflux." Journal of Thrombosis and Haemostasis : JTH, vol. 1, no. 12, 2003, pp. 2663-8.
Johnson GJ, Leis LA, Dunlop PC, et al. The effect of the anorectic agent, d-fenfluramine, and its primary metabolite, d-norfenfluramine, on intact human platelet serotonin uptake and efflux. J Thromb Haemost. 2003;1(12):2663-8.
Johnson, G. J., Leis, L. A., Dunlop, P. C., & Weir, E. K. (2003). The effect of the anorectic agent, d-fenfluramine, and its primary metabolite, d-norfenfluramine, on intact human platelet serotonin uptake and efflux. Journal of Thrombosis and Haemostasis : JTH, 1(12), 2663-8.
Johnson GJ, et al. The Effect of the Anorectic Agent, D-fenfluramine, and Its Primary Metabolite, D-norfenfluramine, On Intact Human Platelet Serotonin Uptake and Efflux. J Thromb Haemost. 2003;1(12):2663-8. PubMed PMID: 14675103.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The effect of the anorectic agent, d-fenfluramine, and its primary metabolite, d-norfenfluramine, on intact human platelet serotonin uptake and efflux. AU - Johnson,G J, AU - Leis,L A, AU - Dunlop,P C, AU - Weir,E K, PY - 2003/12/17/pubmed PY - 2004/2/21/medline PY - 2003/12/17/entrez SP - 2663 EP - 8 JF - Journal of thrombosis and haemostasis : JTH JO - J Thromb Haemost VL - 1 IS - 12 N2 - 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. SN - 1538-7933 UR - https://www.unboundmedicine.com/medline/citation/14675103/The_effect_of_the_anorectic_agent_d_fenfluramine_and_its_primary_metabolite_d_norfenfluramine_on_intact_human_platelet_serotonin_uptake_and_efflux_ L2 - https://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=1538-7933&date=2003&volume=1&issue=12&spage=2663 DB - PRIME DP - Unbound Medicine ER -