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Effect of grapefruit juice on the bioactivation of prasugrel
Author(s) -
Holmberg Mikko T.,
Tornio Aleksi,
Hyvärinen Hanna,
Neuvonen Mikko,
Neuvonen Pertti J.,
Backman Janne T.,
Niemi Mikko
Publication year - 2015
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.12581
Subject(s) - grapefruit juice , prasugrel , pharmacology , chemistry , confidence interval , active metabolite , crossover study , metabolite , pharmacokinetics , clopidogrel , medicine , aspirin , biochemistry , alternative medicine , pathology , placebo
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 200 ml of grapefruit juice or water three times daily for 4 days. On day 3, they ingested a single 10 mg dose of prasugrel with an additional 200 ml 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 (AUC 0–∞ ) 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 (C max ). The C max and AUC 0–∞ 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 0–24 h 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.