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Investigating interactions between phentermine, dexfenfluramine, and 5-HT2C agonists, on food intake in the rat.

Abstract：

RATIONALE: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 dexfenfluramine-phentermine (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 phentermine 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.

journal_name

Psychopharmacology (Berl)

journal_title

Psychopharmacology

authors

Grottick AJ,Whelan K,Sanabria EK,Behan DP,Morgan M,Sage C

doi

10.1007/s00213-014-3829-2

subject

Has Abstract

pub_date

2015-06-01 00:00:00

pages

1973-82

issue

eissn

0033-3158

issn

1432-2072

journal_volume

232

pub_type

杂志文章

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Investigating interactions between phentermine, dexfenfluramine, and 5-HT2C agonists, on food intake in the rat.