Monoamine oxidase inhibition is unlikely to be relevant to the risks associated with phentermine and fenfluramine: a comparison with their abilities to evoke monoamine release

Abstract

OBJECTIVE AND DESIGN: It has been proposed that the anti-obesity agent, phentermine, may act in part via inhibition of monoamine oxidase (MAO). The ability of phentermine to inhibit both MAO_A and MAO_B in vitro has been examined along with that of the fenfluramine isomers, a range of selective serotonin reuptake inhibitors and sibutramine and its active metabolites.

RESULTS: In rat brain, harmaline and lazabemide showed potent and selective inhibition of MAO_A and MAO_B, their respective target enzymes, with IC₅₀ values of 2.3 and 18 nM. In contrast, all other drugs examined were only weak inhibitors of MAO_A and MAO_B with IC₅₀ values for each enzyme in the moderate to high micromolar range. For MAO_A, the IC₅₀ for phentermine was estimated to be 143 µM, that for S(+)-fenfluramine, 265 µM and that for sertraline, 31 µM. For MAO_B, example IC₅₀s were as follows: phentermine (285 µM), S(+)-fenfluramine (800 µM) and paroxetine (16 µM). Sibutramine was unable to inhibit either enzyme, even at its limit of solubility.

CONCLUSION: We therefore suggest that MAO inhibition is unlikely to play a role in the pharmacodynamic properties of any of the tested drugs, including phentermine. Instead, the lack of potency of these drugs as MAO inhibitors is contrasted with their powerful ability either to inhibit the uptake of one or more monoamines (fluoxetine, paroxetine, sertraline, sibutramine's active metabolites) or to evoke the release of one or more monoamines (S(+)-fenfluramine, S(+)-norfenfluramine, phentermine). These differences in mode of action may be linked to the adverse cardiovascular events experienced with some of the releasing agents.