Highly Variable Pharmacokinetics of Tyramine in Humans and Polymorphisms in OCT1, CYP2D6, and MAO-A

Abstract

Tyramine, formed by the decarboxylation of tyrosine, is a natural constituent of numerous food products. As an indirect sympathomimetic, it can have potentially dangerous hypertensive effects. In vitro data indicated that the pharmacokinetics of tyramine possibly depend on the organic cation transporter OCT1 genotype and on the CYP2D6 genotype. Since tyramine is a prototypic substrate of monoamine oxidase A (MAO-A), genetic polymorphisms in MAO-A may also be relevant. The aims of this study were to identify to what extent the interindividual variation in pharmacokinetics and pharmacodynamics of tyramine is determined by genetic polymorphisms in OCT1, CYP2D6, and MAO-A. Beyond that, we wanted to evaluate tyramine as probe drug for the in vivo activity of MAO-A and OCT1. Therefore, the pharmacokinetics, pharmacodynamics, and pharmacogenetics of tyramine were studied in 88 healthy volunteers after oral administration of a 400 mg dose. We observed a strong interindividual variation in systemic tyramine exposure, with a mean AUC of 3.74 min*µg/ml and a high mean CL/F ratio of 107 l/min. On average, as much as 76.8% of the dose was recovered in urine in form of the MAO-catalysed metabolite 4-hydroxyphenylacetic acid (4-HPAA), confirming that oxidative deamination by MAO-A is the quantitatively most relevant metabolic pathway. Systemic exposure of 4-HPAA varied only up to 3-fold, indicating no strong heritable variation in peripheral MAO-A activity. Systolic blood pressure increased by more than 10 mmHg in 71% of the volunteers and correlated strongly with systemic tyramine concentration. In less than 10% of participants, individually variable blood pressure peaks by >40 mmHg above baseline were observed at tyramine concentrations of >60 µg/l. Unexpectedly, the functionally relevant polymorphisms in OCT1 and CYP2D6, including the CYP2D6 poor and ultra-rapid metaboliser genotypes, did not significantly affect tyramine pharmacokinetics or pharmacodynamics. Also, the MOA-A genotypes, which had been associated in several earlier studies with neuropsychiatric phenotypes, had no significant effects on tyramine pharmacokinetics or its metabolism to 4-HPAA. Thus, variation in tyramine pharmacokinetics and pharmacodynamics is not explained by obvious genomic variation, and human tyramine metabolism did not indicate the existence of ultra-low or -high MAO-A activity.

Cellular Uptake of Psychostimulants – Are High- and Low-Affinity Organic Cation Transporters Drug Traffickers?

“…This could lead to intoxication and other adverse effects due to decreased elimination in carriers of alleles with reduced or absent OCT1 activity (e.g., OCT1 variants *2 to *6, which are particularly common in European populations, or OCT1*7 that is frequently found in Africans and Afro-Americans ( Seitz et al, 2015 )). However, a substance being identified as OCT1 substrate in vitro may not necessarily be affected by OCT1 genetic polymorphism in vivo, as illustrated by the example of the indirect sympathomimetic compound tyramine ( Rafehi et al, 2019 ). Thus, the effects of OCT1 genotype on mescaline should be studied in vivo and its clinical implications taken into consideration when developing therapeutic interventions involving mescaline.…”

Overlap and Specificity in the Substrate Spectra of Human Monoamine Transporters and Organic Cation Transporters 1, 2, and 3

“…Uptake by extraneuronal (e.g., hepatic and renal) expressed OCTs might be a critical step in the elimination of these compounds. Exemplarily, the OCT2-mediated uptake and excretion of p -tyramine via the kidney, but also p-tyramine transport by NET, DAT, and OCT3 ( Figure 1 ), might all contribute to the observation that interindividual variation of tyramine pharmacokinetics and pharmacodynamics is not determined at all by the OCT1 genotype [ 75 ].…”

A Questionnaire-Based Survey to Assess the Level of Knowledge and Awareness about Drug–Food Interactions among General Public in Western Saudi Arabia

“…An example of severe DFI involves fermented foods such as cheese and wine, which contain tyramine, which interacts with monoamine oxidase inhibitors (MAOIs, a class of drugs used to treat depression). MAOIs inhibit the breakdown of tyramine, causing buildup of catecholamine (vasoconstrictor), resulting in life-threatening hypertensive crisis [ 9 , 10 ]…”