The effect of monoamine oxidase inhibitors on ‘first-pass’ metabolism of tyramine in dog intestine

Abstract

The role of the intestine in metabolic inactivation of tyramine (TYR) has been studied in an isolated intestinal loop preparation in anaesthetized dogs. In control animals there was extensive metabolism of tyramine on passage through the intestinal wall and p-hydroxyphenylacetic acid ( p-OHPA) was the only metabolite found in venous plasma from the loop (mean ratio p-OHPA/TYR = 5). Oral or intravenous pretreatment with the monoamine oxidase (MAO) inhibitors tranylcypromine or MD780515 significantly lowered the ratio of p-OHPA/TYR (range = 0.2–1.1) measured 3hr after the last dose. Twenty-four hours after the last dose of MAO inhibitor p-OHPA/TYR ratios in dogs pretreated orally with MD780515 had returned to control levels while ratios in dogs pretreated orally with tranylcypromine remained low (mean = 1.6). In vitro rates of deamination of the substrates 5-hydroxytryptamine (selective for the A form of MAO) and β-phenylethylamine (selective for the B form of MAO) in homogenates of intestine paralleled the in vivo findings in most cases. Tranylcypromine produced a nonselective irreversible inhibition of both MAO-A and MAO-B whereas MD780515 was found to be a selective inhibitor of MAO-A and also appeared to be reversible.