Green tea is widely consumed as a beverage and/or dietary supplement worldwide, resulting in the difficulty to avoid the comedication with ticagrelor for acute coronary syndrome (ACS) patients receiving antiplatelet therapy. This study was designed to investigate the effect of the most abundant content in green tea, tea polyphenols on the oral and intravenous pharmacokinetics of ticagrelor in rats and its in vitro metabolism. Rats were orally treated with either saline or tea polyphenol extracts (TPEs) dissolved in saline once daily for 6 consecutive days. On day 6, after the last dose of saline or TPE, ticagrelor was given to the rats orally or intravenously. Plasma samples were collected for pharmacokinetic analysis. Human liver and intestinal microsomes were then used to investigate the inhibition by TPE, as well as its major constituents on the metabolism of ticagrelor to its two metabolites, AR-C124910XX and AR-C133913XX. Apparent kinetic constants and inhibition potency (IC50 ) for each metabolic pathway of each compound were estimated. Oral study indicated that exposure of ticagrelor and AR-C124910XX was significantly decreased after TPE administration, while no significant differences were observed in pharmacokinetic parameters after intravenous administration of ticagrelor. TPE effectively inhibited the metabolism of ticagrelor in vitro, with epigallocatechin-3-gallate as the major constituent responsible for the observed inhibitory effects in human liver microsomes and intestinal microsomes (IC50 = 4.23 ± 0.18 µM). Caution should be taken for ACS patients receiving ticagrelor therapy with daily drinking of green tea. PRACTICAL APPLICATION: Potential interactions between tea polyphenols and ticagrelor were revealed for the first time. Results can provide suggestions for clinicians to optimize the dosing of ticagrelor while they are in the face of ACS patients receiving ticagrelor therapy, who also take green tea or its related products in their daily life.

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茶多酚对替格瑞洛大鼠口服和静脉药代动力学及其体外代谢的影响

绿茶在世界范围内被广泛用作饮料和/或膳食补充剂，导致难以避免替格瑞洛对接受抗血小板治疗的急性冠状动脉综合征 (ACS) 患者的联合用药。本研究旨在研究绿茶中含量最丰富的茶多酚对替格瑞洛大鼠口服和静脉内药代动力学及其体外代谢的影响。连续 6 天每天一次用盐水或茶多酚提取物 (TPE) 对大鼠进行口服治疗。在第 6 天，在最后一剂生理盐水或 TPE 后，口服或静脉内给予大鼠替格瑞洛。收集血浆样品用于药代动力学分析。然后使用人肝和肠微粒体研究 TPE 的抑制作用，以及其对替格瑞洛代谢为其两种代谢物 AR-C124910XX 和 AR-C133913XX 的主要成分。估计了每种化合物的每种代谢途径的表观动力学常数和抑制效力(IC50)。口服研究表明，TPE给药后替格瑞洛和AR-C124910XX的暴露量显着降低，而替格瑞洛静脉给药后的药代动力学参数未观察到显着差异。TPE 在体外有效抑制替格瑞洛的代谢，表没食子儿茶素-3-没食子酸酯是在人肝微粒体和肠微粒体中观察到抑制作用的主要成分（IC50 = 4.23 ± 0.18 µM）。接受替格瑞洛治疗并每天饮用绿茶的 ACS 患者应谨慎。实际应用：首次揭示了茶多酚与替格瑞洛之间的潜在相互作用。研究结果可为临床医生在面对接受替格瑞洛治疗且日常生活中也服用绿茶或其相关产品的ACS患者时优化替格瑞洛的剂量提供建议。