Abe Osamu, Ono Tomoyuki, Sato Hideyuki, Müller Fabian, Ogata Hiroshi, Miura Itaru, Shikama Yayoi, Yabe Hirooki, Onoue Satomi, Fromm Martin F, Kimura Junko, Misaka Shingen
Department of Pharmacology, School of Medicine, Fukushima Medical University, 1 Hikarigaoka, Fukushima, 960-1295, Japan.
Department of Neuropsychiatry, School of Medicine, Fukushima Medical University, Fukushima, Japan.
Eur J Clin Pharmacol. 2018 Jun;74(6):775-783. doi: 10.1007/s00228-018-2436-2. Epub 2018 Feb 26.
The aim of the present study is to investigate a possible role of a single dose of (-)-epigallocatechin gallate (EGCG), the major catechin in green tea, for the pharmacokinetic interaction between green tea and nadolol in humans.
In a randomized three-phase crossover study, 13 healthy volunteers received single doses of 30 mg nadolol orally with water (control), or an aqueous solution of EGCG-concentrated green tea extract (GTE) at low or high dose. Plasma concentrations and urinary excretion of nadolol were determined up to 48 h. In addition, blood pressure and pulse rate were monitored. In vitro transport kinetic experiments were performed using human embryonic kidney 293 cells stably expressing organic anion transporting polypeptide (OATP)1A2 to evaluate the inhibitory effect of EGCG on OATP1A2-mediated substrate transport.
Single coadministration of low and high dose GTE significantly reduced the plasma concentrations of nadolol. The geometric mean ratios with 90% CI for area under the plasma concentration-time curves from 0 to infinity of nadolol were 0.72 (0.56-0.87) for the low and 0.60 (0.51-0.69) for the high dose. There were no significant differences in T, elimination half-life, and renal clearance between GTE and water phases. No significant changes were observed for blood pressure and pulse rate between phases. EGCG competitively inhibited OATP1A2-mediated uptake of sulphobromophthalein and nadolol with K values of 21.6 and 19.4 μM, respectively.
EGCG is suggested to be a key contributor to the interaction of green tea with nadolol. Moreover, even a single coadministration of green tea may significantly affect nadolol pharmacokinetics.
本研究旨在探讨单剂量（-）-表没食子儿茶素没食子酸酯（EGCG）（绿茶中的主要儿茶素）在人体中对绿茶与纳多洛尔之间药代动力学相互作用的潜在作用。
在一项随机三相交叉研究中，13名健康志愿者口服单剂量30mg纳多洛尔（用水送服，作为对照），或低剂量或高剂量的EGCG浓缩绿茶提取物（GTE）水溶液。在48小时内测定纳多洛尔的血浆浓度和尿排泄量。此外，监测血压和脉搏率。使用稳定表达有机阴离子转运多肽（OATP）1A2的人胚肾293细胞进行体外转运动力学实验，以评估EGCG对OATP1A2介导的底物转运的抑制作用。
低剂量和高剂量GTE的单次联合给药显著降低了纳多洛尔的血浆浓度。纳多洛尔血浆浓度-时间曲线下面积从0至无穷大的几何平均比值及90%置信区间，低剂量组为0.72（0.56 - 0.87），高剂量组为0.60（0.51 - 0.69）。GTE组和水相组之间的达峰时间、消除半衰期和肾清除率无显著差异。各阶段之间血压和脉搏率未观察到显著变化。EGCG竞争性抑制OATP1A2介导的磺溴酞钠和纳多洛尔摄取，其K值分别为21.6和19.4μM。
EGCG被认为是绿茶与纳多洛尔相互作用的关键因素。此外，即使单次联合服用绿茶也可能显著影响纳多洛尔的药代动力学。
