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

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 muM, that for S(+)-fenfluramine, 265 muM and that for sertraline, 31 muM. For MAO(B), example IC(50)s were as follows: phentermine (285 muM), S(+)-fenfluramine (800 muM) and paroxetine (16 muM). 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.