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Psychopharmacology (2015) 232:19731982 DOI 10.1007/s00213-014-3829-2
ORIGINAL INVESTIGATION
Investigating interactions between phentermine, dexfenfluramine, and 5-HT2C agonists, on food intake in the rat
Andrew J. Grottick & Kevin Whelan & Erin K. Sanabria &
Dominic P. Behan & Michael Morgan & Carleton Sage
Received: 2 October 2014 /Accepted: 20 November 2014 /Published online: 20 December 2014 # The Author(s) 2014. This article is published with open access at Springerlink.com
AbstractRationale Synergistic or supra-additive interactions between the anorectics (dex)fenfluramine and phentermine have been reported previously in the rat and in the clinic. Studies with 5-HT2C antagonists and 5-HT2C knockouts have demonstrated dexfenfluramine hypophagia in the rodent to be mediated by actions at the 5-HT2C receptor. Given the recent FDA approval of the selective 5-HT2C agonist lorcaserin (BELVIQ) for weight management, we investigated the interaction between phentermine and 5-HT2C agonists on food intake.
Objectives This study aims to confirm dexfenfluraminephentermine (dex-phen) synergy in a rat food intake assay, to extend these findings to other 5-HT2C agonists, and to determine whether pharmacokinetic interactions could explain synergistic findings with particular drug combinations. Methods Isobolographic analyses were performed in which phentermine was paired with either dexfenfluramine, the 5-HT2C agonist AR630, or the 5-HT2C agonist lorcaserin, and inhibition of food intake measured in the rat. Subsequent studies assessed these same phentermine-drug pair combinations spanning both the full effect range and a range of fixed ratio drug combinations. Satellite groups received single doses of each drug either alone or in combination with phentermine, and free brain concentrations were measured.
Results Dex-phen synergy was confirmed in the rat and extended to the 5-HT2C agonist AR630. In contrast, although some synergistic interactions between lorcaserin and phenter-mine were observed, these combinations were largely additive. Synergistic interactions between phentermine and dexfenfluramine or AR630 were accompanied by combination-induced increases in brain levels of phentermine.
Conclusions Dex-phen synergy in the rat is caused by a pharmacokinetic interaction, resulting in increased central concentrations of phentermine.
Keywords Synergy . BELVIQ . Lorcaserin . Isobologram . Fen-phen
Introduction
Fenfluramine (Pondimin) and dexfenfluramine (Redux) are anorectic agents which act to enhance serotonergic transmission both through inhibition of 5-HT reuptake by the parent compounds, and through their major circulating des-ethylated metabolite, (dex)norfenfluramine, which is a 5-HT reuptake inhibitor, a 5-HT and noradrenaline releasing agent, and...