title: Effect of grapefruit juice on the bioactivation of prasugrel.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Mikko T
authors.initials: MT
authors.lastname: Holmberg
authors.affiliation: Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Aleksi
authors.initials: A
authors.lastname: Tornio
authors.affiliation: Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Hanna
authors.initials: H
authors.lastname: Hyvärinen
authors.affiliation: Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Mikko
authors.initials: M
authors.lastname: Neuvonen
authors.affiliation: Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Pertti J
authors.initials: PJ
authors.lastname: Neuvonen
authors.affiliation: Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Janne T
authors.initials: JT
authors.lastname: Backman
authors.affiliation: Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Mikko
authors.initials: M
authors.lastname: Niemi
mesh_terms: D065767:Activation, Metabolic / Q000187:drug effects; D001628:Beverages / Q000009:adverse effects*; D001792:Blood Platelets / Q000187:drug effects; D032083:Citrus paradisi / Q000009:adverse effects*; D018592:Cross-Over Studies; D005260:Female; D018565:Food-Drug Interactions; D006801:Humans; D008297:Male; D010975:Platelet Aggregation Inhibitors / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D000068799:Prasugrel Hydrochloride / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D011355:Prodrugs / Q000378:metabolism* / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D010975:Platelet Aggregation Inhibitors; D011355:Prodrugs; D000068799:Prasugrel Hydrochloride
keywords: cytochrome P450 3A4; drug interaction; grapefruit juice; prasugrel