Rafehi Muhammad, Faltraco Frank, Matthaei Johannes, Prukop Thomas, Jensen Ole, Grytzmann Aileen, Blome Felix G, Berger Ralf Günter, Krings Ulrich, Vormfelde Stefan V, Tzvetkov Mladen V, Brockmöller Jürgen
Institute of Clinical Pharmacology, University Medical Center Göttingen, Georg-August University, Göttingen, Germany.
Institute of Food Chemistry, Leibniz University, Hannover, Germany.
Front Pharmacol. 2019 Oct 30;10:1297. doi: 10.3389/fphar.2019.01297. eCollection 2019.
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. 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 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.
酪胺由酪氨酸脱羧形成，是众多食品中的天然成分。作为一种间接拟交感神经药，它可能具有潜在危险的高血压效应。数据表明，酪胺的药代动力学可能取决于有机阳离子转运体OCT1基因型和CYP2D6基因型。由于酪胺是单胺氧化酶A（MAO-A）的典型底物，MAO-A的基因多态性可能也与之相关。本研究的目的是确定OCT1、CYP2D6和MAO-A的基因多态性在多大程度上决定了酪胺药代动力学和药效学的个体间差异。除此之外，我们想评估酪胺作为MAO-A和OCT1活性的探针药物。因此，在88名健康志愿者口服400mg剂量的酪胺后，对其药代动力学、药效学和药物遗传学进行了研究。我们观察到全身酪胺暴露存在强烈的个体间差异，平均AUC为3.74分钟*微克/毫升，平均CL/F比值较高，为107升/分钟。平均而言，高达76.8%的剂量以MAO催化的代谢物4-羟基苯乙酸（4-HPAA）的形式在尿液中回收，这证实了MAO-A的氧化脱氨是数量上最相关的代谢途径。4-HPAA的全身暴露仅变化了3倍，表明外周MAO-A活性没有强烈的遗传变异。71%的志愿者收缩压升高超过10mmHg，且与全身酪胺浓度密切相关。在不到10%的参与者中，酪胺浓度>60微克/升时观察到个体可变的血压峰值比基线高出>40mmHg。出乎意料的是，OCT1和CYP2D6中功能相关的多态性，包括CYP2D6慢代谢和超快代谢基因型，并未显著影响酪胺的药代动力学或药效学。此外，在几项早期研究中与神经精神表型相关的MOA-A基因型，对酪胺的药代动力学或其代谢为4-HPAA没有显著影响。因此，酪胺药代动力学和药效学的差异无法用明显的基因组变异来解释，并且人类酪胺代谢并未表明存在超低或超高的MAO-A活性。
