Effect of grapefruit juice on the bioactivation of prasugrel

Abstract

Aims The P2Y12 inhibitor prasugrel is a prodrug, which is activated after its initial hydrolysis partly by cytochrome P450 (CYP) 3A4. Grapefruit juice, a strong inactivator of intestinal CYP3A4, greatly reduces the activation and antiplatelet effects of clopidogrel. The aim of this study was to investigate the effects of grapefruit juice on prasugrel. Methods In a randomized crossover study, seven healthy volunteers ingested 200ml of grapefruit juice or water three times daily for 4days. On day 3, they ingested a single 10mg dose of prasugrel with an additional 200ml of grapefruit juice or water. Plasma concentrations of prasugrel metabolites and the antiplatelet effect were measured. Results Grapefruit juice increased the geometric mean area under the plasma concentration-time curve (AUC0-) of the primary, inactive metabolite of prasugrel to 164% of the control value (95% confidence interval 122-220%, P = 0.008), without a significant effect on its peak plasma concentration (Cmax). The Cmax and AUC0- of the secondary, active metabolite were decreased to 51% (95% confidence interval 32-84%, P = 0.017) and 74% of the control value (95% confidence interval 60-91%, P = 0.014) by grapefruit juice (P < 0.05). The average platelet inhibition, assessed with the VerifyNow® method at 0-24h after prasugrel intake, was 5 percentage points (95% confidence interval 1-10 percentage points) lower in the grapefruit juice phase than in the water phase (P = 0.034). Conclusions Grapefruit juice reduces the bioactivation of prasugrel, but this has only a limited effect on the antiplatelet effect of prasugrel.