Ticagrelor is a first-line clinical drug for the treatment of acute coronary syndrome, but its oral bioavailability is relatively low. Flavonoids (polyphenol compounds commonly found in plant foods) seriously affect human metabolism and health. This study compared the effects of quercetin, luteolin and catechin on the pharmacokinetic parameters of ticagrelor and found that quercetin can significantly increase the C_max and area under the curve from time zero to 36 h (AUC_0–36) of ticagrelor, that is, quercetin can enhance the bioavailability of ticagrelor, but luteolin and catechin cannot. The difference between the ticagrelor group and the combination of quercetin and ticagrelor was analyzed through untargeted metabolomics methods and multivariate data analysis, which identified changes in the levels of seven metabolites (deoxycholic acid, taurocholic acid, glycocholic acid, glycoursodeoxycholic acid, tryptophan, phenylalanine and kynurenine). Based on the changes of these metabolites, we found that the metabolic pathways of phenylalanine, tyrosine and tryptophan and the biosynthetic pathway of bile acids were changed. A metabolomics study revealed that quercetin improves the oral bioavailability of ticagrelor and that this might rely on changing the metabolic pathways of phenylalanine, tyrosine and tryptophan and the biosynthetic pathway of bile acids. The research results at the metabolic level provide us with a strong basis and direction for further exploring the mechanism underlying quercetin’s ability to enhance the bioavailability of ticagrelor, and this may be useful for finding new agents that enhance the bioavailability.

中文翻译：

---

非靶向代谢组学揭示了槲皮素提高替格瑞洛生物利用度的机制。

替格瑞洛是治疗急性冠脉综合征的一线临床药物，但其口服生物利用度较低。类黄酮（植物性食物中常见的多酚化合物）严重影响人体新陈代谢和健康。本研究比较了槲皮素、木犀草素和儿茶素对替格瑞洛药代动力学参数的影响，发现槲皮素可以显着增加从零到36小时的C _{max和曲线下面积（AUC 0-36})的替格瑞洛，即槲皮素可以提高替格瑞洛的生物利用度，而木犀草素和儿茶素则不能。通过非靶向代谢组学方法和多变量数据分析分析了替格瑞洛组与槲皮素和替格瑞洛联合用药之间的差异，确定了七种代谢物（脱氧胆酸、牛磺胆酸、甘氨胆酸、甘氨去氧胆酸、色氨酸、苯丙氨酸和犬尿氨酸）。基于这些代谢物的变化，我们发现苯丙氨酸、酪氨酸和色氨酸的代谢途径和胆汁酸的生物合成途径发生了变化。一项代谢组学研究表明，槲皮素提高了替格瑞洛的口服生物利用度，这可能依赖于改变苯丙氨酸的代谢途径，酪氨酸和色氨酸以及胆汁酸的生物合成途径。代谢水平的研究成果为我们进一步探索槲皮素提高替格瑞洛生物利用度的机制提供了强有力的基础和方向，这可能有助于寻找提高生物利用度的新药物。