Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki, Finland.
Br J Clin Pharmacol. 2013 Jun;75(6):1488-96. doi: 10.1111/bcp.12026.
This study examined the effects of grapefruit juice on the new P2Y12 inhibitor ticagrelor, which is a substrate of CYP3A4 and P-glycoprotein.
In a randomized crossover study, 10 healthy volunteers ingested 200 ml of grapefruit juice or water thrice daily for 4 days. On day 3, they ingested a single 90 mg dose of ticagrelor.
Grapefruit juice increased ticagrelor geometric mean peak plasma concentration (Cmax ) to 165% (95% confidence interval 147, 184%) and area under the concentration-time curve (AUC(0,∞)) to 221% of control (95% confidence interval 200, 245%). The Cmax and AUC(0,34 h) (P < 0.05) but not the AUC(0,∞) of the active metabolite C12490XX were decreased significantly. Grapefruit juice had a minor effect on ticagrelor elimination half-life prolonging it from 6.7 to 7.2 h (P = 0.036). In good correlation with the elevated plasma ticagrelor concentrations, grapefruit juice enhanced the antiplatelet effect of ticagrelor, assessed with VerifyNow® and Multiplate® methods, and postponed the recovery of platelet reactivity.
Grapefruit juice increased ticagrelor exposure by more than two-fold, leading to an enhanced and prolonged ticagrelor antiplatelet effect. The grapefruit juice-ticagrelor interaction seems clinically important and indicates the significance of intestinal metabolism to ticagrelor pharmacokinetics.
本研究旨在探讨葡萄柚汁对新型 P2Y12 抑制剂替格瑞洛的影响，后者是 CYP3A4 和 P-糖蛋白的底物。
在一项随机交叉研究中，10 名健康志愿者每日分 3 次服用 200 毫升葡萄柚汁或水，连续 4 天。在第 3 天，他们单次服用 90 毫克替格瑞洛。
葡萄柚汁使替格瑞洛的几何平均峰血浆浓度（Cmax）增加至 165%（95%置信区间 147，184%），曲线下面积（AUC(0,∞)）增加至 221%（95%置信区间 200，245%）。Cmax 和 AUC(0,34 h)（P<0.05）但不是活性代谢物 C12490XX 的 AUC(0,∞)显著降低。葡萄柚汁对替格瑞洛的消除半衰期影响较小，将其从 6.7 小时延长至 7.2 小时（P=0.036）。与替格瑞洛血浆浓度升高良好相关，葡萄柚汁增强了替格瑞洛的抗血小板作用，这通过 VerifyNow®和 Multiplate®方法评估，并推迟了血小板反应性的恢复。
葡萄柚汁使替格瑞洛暴露量增加了两倍以上，导致替格瑞洛抗血小板作用增强和延长。葡萄柚汁与替格瑞洛的相互作用在临床上似乎很重要，表明肠道代谢对替格瑞洛药代动力学的重要性。
