Antihistamine-monoamine oxidase inhibitor interaction in rabbits

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Abstract
The ability of a drug to produce a fatal hyperpyrexia in rabbits pretreated with a monoamine oxidase inhibitor (MAOI) may be predictive of a serious clinical drug-drug interaction. These interactions appear to be due to 5-hydroxytryptamine (5-HT) potentiation. Since some antihistamines have been shown to block the neuronal 5-HT uptake, several antihistamines were tested in phenelzine-pretreated rabbits. The alkylamines (dexchlorpheniramine, chlorpheniramine, dexbrompheniramine, brompheniramine and pheniramine) and the ethylenediamines (mepyramine and tripelennamine) were active in producing a fatal hyperpyrexia in the MAOI-pretreated rabbits. Diphenhydramine and triprolidine produced a fatal hyperpyrexia in approximately one half of the animals tested. The mechanism responsible for the interaction between chlorpheniramine, a representative of the active compounds, and phenelzine appears to be 5-HT potentiation. Antihistamines that did not produce a fatal hyperpyrexia in the phenelzine pretreated rabbits were: phenyltoloxamine, promethazine, methdilazine, trimeprazine, meclizine, chlorcyclizine, cyproheptadine, phenindamine and dimethpyrindene. The potential use of the active compounds as antidepressants is also discussed.