title: Investigating interactions between phentermine, dexfenfluramine, and 5-HT2C agonists, on food intake in the rat.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Arena Pharmaceuticals Inc, 6154 Nancy Ridge Drive, San Diego, CA, 92121, USA, agrottick@arenapharm.com.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Grottick
authors.forename: Kevin
authors.initials: K
authors.lastname: Whelan
authors.forename: Erin K
authors.initials: EK
authors.lastname: Sanabria
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Behan
authors.forename: Michael
authors.initials: M
authors.lastname: Morgan
authors.forename: Carleton
authors.initials: C
authors.lastname: Sage
mesh_terms: D000818:Animals; D001067:Appetite Depressants / Q000493:pharmacokinetics / Q000494:pharmacology*; D020372:Dexfenfluramine / Q000493:pharmacokinetics / Q000494:pharmacology*; D004357:Drug Synergism; D004435:Eating / Q000187:drug effects*; D005277:Fenfluramine / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D010645:Phentermine / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044405:Receptor, Serotonin, 5-HT2C / Q000187:drug effects*; D058826:Serotonin 5-HT2 Receptor Agonists / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D001067:Appetite Depressants; D044405:Receptor, Serotonin, 5-HT2C; D058826:Serotonin 5-HT2 Receptor Agonists; D005277:Fenfluramine; D010645:Phentermine; D020372:Dexfenfluramine