Aminorex, fenfluramine, and chlorphentermine are serotonin transporter substrates - Implications for primary pulmonary hypertension

Citation
Rb. Rothman et al., Aminorex, fenfluramine, and chlorphentermine are serotonin transporter substrates - Implications for primary pulmonary hypertension, CIRCULATION, 100(8), 1999, pp. 869-875
Citations number
46
Categorie Soggetti
Cardiovascular & Respiratory Systems","Cardiovascular & Hematology Research
Journal title
CIRCULATION
ISSN journal
00097322 → ACNP
Volume
100
Issue
8
Year of publication
1999
Pages
869 - 875
Database
ISI
SICI code
0009-7322(19990824)100:8<869:AFACAS>2.0.ZU;2-P
Abstract
Background-Coadministration of phentermine and fenfluramine (phen/fen) effe ctively treats obesity and possibly addictive disorders. The association of fenfluramine and certain ther anorexic agents with serious side effects, s uch as cardiac valvulopathy and primary pulmonary hypertension (PPH), limit s the clinical utility of these drugs. Development of new medications that produce neurochemical effects like phen/fen without causing unwanted side e ffects would be a significant therapeutic breakthrough. Methods and Results-We tested the hypothesis that fenfluramine (and other a norexic agents) might increase the risk of PPH through interactions with se rotonin (5-HT) transporters. Because 5-HT transporter proteins in the lung and brain are identical, we examined, in rat brain, the effects of selected drugs on 5-HT efflux in vivo and monoamine transporters in vitro as a gene ralized index of transporter function. Our data show that drugs known or su spected to increase the risk of PPH (eg, aminorex; fenfluramine, and chlorp hentermine) are 5-HT transporter substrates, whereas drugs that have not be en shown to increase the risk of PPH are less potent in this regard. Conclusions-We speculate that medications that are 5-HT transporter substra tes get translocated into pulmonary cells where, depending on the degree of drug retention, their intrinsic drug toxicity, and individual susceptibili ty, PPH could develop as a response to high levels of these drugs or metabo lites. Emerging evidence suggests that it is possible to develop transporte r substrates devoid of adverse side effects. Such medications could have th erapeutic application in the management of obesity, drug dependence, depres sion, and other disorders.