Inhibition of serotonin uptake and the toxic interaction between meperidine and monoamine oxidase inhibitors

Abstract

The possibility that inhibition of serotonin uptake by meperidine was the basis for the greater toxicity of the drug in animals treated with monoamine oxidase inhibitors was investigated by comparing meperidine to a new potent inhibitor of serotonin uptake, Lilly 110140 (3-[ p-trifluoromethylphenoxy]- N-methyl-3-phenylpropylamine hydrochloride). The blockade of 4-chloroamphetamine-induced depletion of brain serotonin was used as a measure of inhibition of uptake into serotoninergic neurons. With meperidine, the doses required to inhibit that uptake were approximately equal to doses that were lethal in tranylcypromine-pretreated mice. Lilly 110140, on the other hand, inhibited uptake at doses less than 1 100 of those that were toxic in tranylcypromine-pretreated mice. These findings show that inhibition of uptake into serotoninergic neurons does not in itself lead to toxic interactions with monoamine oxidase inhibitors.