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
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.