Grapefruit juice markedly increases the plasma concentrations and antiplatelet effects of ticagrelor in healthy subjects.

Aim This study examined the effects of grapefruit juice on the new P2Y12 inhibitor ticagrelor, which is a substrate of CYP3A4 and P-glycoprotein. Methods In a randomized crossover study, 10 healthy volunteers ingested 200ml of grapefruit juice or water thrice daily for 4 days. On day 3, they ingested a single 90mg dose of ticagrelor. Results Grapefruit juice increased ticagrelor geometric mean peak plasma concentration (Cmax) to 165% (95% confidence interval 147, 184%) and area under the concentrationtime curve (AUC(0,)) to 221% of control (95% confidence interval 200, 245%). The Cmax and AUC(0,34h) (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 7.2h (P = 0.036). In good correlation with the elevated plasma ticagrelor concentrations, grapefruit juice enhanced the antiplatelet effect of ticagrelor, assessed with VerifyNow (R) and Multiplate (R) methods, and postponed the recovery of platelet reactivity. Conclusions Grapefruit juice increased ticagrelor exposure by more than two-fold, leading to an enhanced and prolonged ticagrelor antiplatelet effect. The grapefruit juiceticagrelor interaction seems clinically important and indicates the significance of intestinal metabolism to ticagrelor pharmacokinetics.