The Effects of Amiflamine, a Reversible MAO-A Inhibitor, on the First Pass Metabolism of Tyramine in Dog Intestine

Abstract

Abstract-The effects of amiflamine on tyramine deamination were studied using isolated loops of intestine in anesthetized dogs.In the pretreatment experiment, dogs were dosed with amiflamine (3.5 mg/kg/day) once daily for 3 days, with the study being carried out 3 hr after the final dose.[14C] Tyramine (50 mg and 50 /cCi) in 10 ml of normal saline was introduced into the isolated loops of gut, and tyramine and p-hydroxyphenylacetic acid in the venous blood were separated by HPLC and measured by scintillation spectrometry.In the untreated dogs, ap proximately 15% of the tyramine passed through the gut wall unchanged. When tyramine and amiflamine (0.06 to 3.5 mg/kg) were administered simultaneously to the gut loop, about 27 to 65% of the tyramine passed through the gut wall un changed.On the contrary, after pretreatment with amiflamine for 3 days, percen tage of tyramine passing through the gut wall was not increased in comparison with the control.These results suggest that pretreatment with amiflamine does not produce drug concentrations in the lining cells of the gut sufficient to effectively inhibit the deamination of oral tyramine, which is administered at least 3 hr after the final dose of amiflamine.Monoamine oxidase (MAO) inhibitors are clinically used as antidepressants, but limitation of extensive use of these drugs is due to hypertensive crisis (cheese effect) occurring when the patient ingests certain foodstuff containing vasoactive amines such as tyramine. Circulating tyramine liberates noradrenaline from nerve endings and produces the pressor effect (1 ). It is generally assumed that such hypertensive crises occur as a result of inhibition of MAO in the intestine and to a lesser extent in the liver, allowing active tyramine to enter the systemic circulation, and of inhibition of intraneural

Individual Variation in First-Pass Metabolism

“…In these studies, the extent of interaction in the gut wall may have been overestimated because the liver contribution was not taken into account. Although there are other similar examples cited in the literature, such as interactions between morphine and fenoterol (Koster et al 1985), morphine and orciprenaline (meta proterenol) [Koster et al 1985], tyramine and monoamine oxidase (MAO) inhibitors (Yasuhara et al 1986), etc., again the significance in the alteration of first pass through the gut is not known, because the liver contribution was not quantified.…”