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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2019.01297

Highly variable pharmacokinetics of tyramine in humans and polymorphisms in OCT1, CYP2D6, and MAO-A

 Muhammad Rafehi1*, Frank Faltraco1, 2,  Johannes Matthaei1, Thomas Prukop1, Ole Jensen1, Aileen Grytzmann1, Felix G. Blome1,  Ralf G. Berger3, Ulrich Krings3, Stefan V. Vormfelde1, 4,  Mladen V. Tzvetkov1, 5 and  Jürgen Brockmöller1
  • 1Institute of Clinical Pharmacology, University Medical Center Göttingen, Germany
  • 2University Hospital Rostock, Germany
  • 3Leibniz University Hannover, Germany
  • 4Novartis (Switzerland), Switzerland
  • 5Institute of Pharmacology, University of Greifswald, Germany

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.

Keywords: biogenic amine, CYP2D6, MAO, Monoamine Oxidase, OCT1, Pressor response, SLC22A1, Tyramine

Received: 07 Aug 2019; Accepted: 10 Oct 2019.

Copyright: © 2019 Rafehi, Faltraco, Matthaei, Prukop, Jensen, Grytzmann, Blome, Berger, Krings, Vormfelde, Tzvetkov and Brockmöller. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Muhammad Rafehi, Institute of Clinical Pharmacology, University Medical Center Göttingen, Göttingen, 37075, Lower Saxony, Germany, muhammad.rafehi@med.uni-goettingen.de