M. Holmberg, A. Tornio, H. Hyvärinen, M. Neuvonen, P. J. Neuvonen, J. T. Backman, M. Niemi; University of Helsinki and HUSLAB, Helsinki, Finland

BACKGROUND: Cytochrome P450 (CYP) 3A4 participates in the bioactivation of the P2Y12 inhibitor prasugrel. Grapefruit juice intake leads to strong inhibition of intestinal CYP3A4. Grapefruit juice was recently found to impair the bioactivation and anti-platelet effects of clopidogrel. On the other hand, grapefruit juice inhibits the first-pass metabolism and increases the anti-platelet effects of ticagrelor. The aim of this study was to investigate possible effects of grapefruit juice on prasugrel.
METHODS: In a randomized crossover study, seven healthy volunteers ingested 200 ml of grapefruit juice or water thrice daily for four days. On day three, they ingested a single 10 mg dose of prasugrel with an additional 200 ml of grapefruit juice or water. Plasma concentrations of prasugrel and its active metabolite were measured up to 48 h, and antiplatelet effects were assessed with turbidimetric optical detection (VerifyNow® P2Y12 assay, Accumetrics, San Diego, CA).
RESULTS: Grapefruit juice decreased prasugrel active metabolite geometric mean peak plasma concentration (Cmax) to 51% (95% confidence interval, 32-84%; P<0.05) and area under the concentration-time curve (AUC0-∞) to 74% of control (95% confidence interval, 60-91%; P<0.05). However, there was no significant difference in the antiplatelet effect of prasugrel between the grapefruit juice and water phases. The average platelet inhibition was 30% in the grapefruit juice and 33% in the water phase (95% confidence interval for difference, -9 to +3%).
CONCLUSION: Grapefruit juice moderately reduces the bioactivation of prasugrel. However, it has no major effect on the antiplatelet effect of prasugrel. Thus, intestinal first-pass metabolism via CYP3A4 is not crucial for the bioactivation of prasugrel.