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
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 IC(50) values of 2.3 and 18 nM. In contrast, all other drugs examined were only weak inhibitors of MAO(A) and MAO(B) with IC(50) values for each enzyme in the moderate to high micromolar range. For MAO(A), the IC(50) for phentermine was estimated to be 143 microM, that for S(+)-fenfluramine, 265 microM and that for sertraline, 31 microM. For MAO(B), example IC(50)s were as follows: phentermine (285 microM), S(+)-fenfluramine (800 microM) and paroxetine (16 microM). Sibutramine was unable to inhibit either enzyme, even at its limit of solubility.


CONCLUSIONS
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.
Kilpatrick
I C
IC
Knoll Limited Research and Development, Nottingham, UK. Ian.Kilpatrick@knoll.co.uk
Traut
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Heal
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D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D002318:Cardiovascular Diseases / Q000139:chemically induced* / Q000209:etiology; D005277:Fenfluramine / Q000494:pharmacology*; D008297:Male; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D010645:Phentermine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017367:Selective Serotonin Reuptake Inhibitors
D005277:Fenfluramine; D008995:Monoamine Oxidase; D008996:Monoamine Oxidase Inhibitors; D010645:Phentermine; D017367:Selective Serotonin Reuptake Inhibitors