Oral absorption and concentration-effect relationship of tyramine with and without cimoxatone, a type-A specific inhibitor of monoamine oxidase.

Abstract

The mechanism of increased sensitivity to oral tyramine in patients taking monoamine oxidase inhibitors was investigated by measurement of plasma norepinephrine and tyramine with a reversible, monoamine oxidase form A selective inhibitor, cimoxatone. In the first open study, the pressor activity of 80 mg oral tyramine after cimoxatone was of the order of that of 800 mg without the drug. In a second double-blind study, the equivalent tyramine dose was between 400 and 800 mg. Absorption of unmetabolized tyramine increased in the presence of cimoxatone. Peak plasma concentration of tyramine after an 80-mg dose was approximately three times that of placebo when given after cimoxatone. The plasma tyramine concentration required to induce a similar pressor effect averaged 130.5 ng ml-1 without pretreatment and 17.4 ng ml-1 after cimoxatone in the open study. Another plasma concentration, 16.4 ng ml-1, elicited a lower pressor effect in the double-blind study. The increased sensitivity to oral tyramine has two components: decreased presystemic clearance in the gut wall and increased sensitivity to circulating tyramine. The tyramine dose required to induce a pressor effect after cimoxatone is relatively higher than after irreversible inhibitors such as phenelzine. This may reflect the dose of cimoxatone used, the activity of monoamine oxidase form B (MAO-B) in the gut and liver or displacement of the predominantly reversible and predominantly competitive inhibitor, cimoxatone, from the enzyme by a high local tyramine concentration.