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Abstract
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-HT^sub 2C^ antagonists and 5-HT^sub 2C^ knockouts have demonstrated dexfenfluramine hypophagia in the rodent to be mediated by actions at the 5-HT^sub 2C^ receptor. Given the recent FDA approval of the selective 5-HT^sub 2C^ agonist lorcaserin (BELVIQ) for weight management, we investigated the interaction between phentermine and 5-HT^sub 2C^ agonists on food intake.
This study aims to confirm dexfenfluramine-phentermine (dex-phen) synergy in a rat food intake assay, to extend these findings to other 5-HT^sub 2C^ agonists, and to determine whether pharmacokinetic interactions could explain synergistic findings with particular drug combinations.
Isobolographic analyses were performed in which phentermine was paired with either dexfenfluramine, the 5-HT^sub 2C^ agonist AR630, or the 5-HT^sub 2C^ 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.
Dex-phen synergy was confirmed in the rat and extended to the 5-HT^sub 2C^ 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.
Dex-phen synergy in the rat is caused by a pharmacokinetic interaction, resulting in increased central concentrations of phentermine.