title: Grapefruit juice markedly increases the plasma concentrations and antiplatelet effects of ticagrelor in healthy subjects.
abstract: OBJECTIVE
  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 200 ml of grapefruit juice or water thrice daily for 4 days. On day 3, they ingested a single 90 mg 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 concentration-time curve (AUC(0,∞)) to 221% of control (95% confidence interval 200, 245%). The Cmax and AUC(0,34 h) (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 7.2 h (P = 0.036). In good correlation with the elevated plasma ticagrelor concentrations, grapefruit juice enhanced the antiplatelet effect of ticagrelor, assessed with VerifyNow® and Multiplate® 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 juice-ticagrelor interaction seems clinically important and indicates the significance of intestinal metabolism to ticagrelor pharmacokinetics.
authors.affiliation: Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki, Finland.
authors.forename: Mikko T
authors.initials: MT
authors.lastname: Holmberg
authors.forename: Aleksi
authors.initials: A
authors.lastname: Tornio
authors.forename: Lotta
authors.initials: L
authors.lastname: Joutsi-Korhonen
authors.forename: Mikko
authors.initials: M
authors.lastname: Neuvonen
authors.forename: Pertti J
authors.initials: PJ
authors.lastname: Neuvonen
authors.forename: Riitta
authors.initials: R
authors.lastname: Lassila
authors.forename: Mikko
authors.initials: M
authors.lastname: Niemi
authors.forename: Janne T
authors.initials: JT
authors.lastname: Backman
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000241:Adenosine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000328:Adult; D019540:Area Under Curve; D001628:Beverages; D001792:Blood Platelets; D032083:Citrus paradisi; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D005260:Female; D018565:Food-Drug Interactions; D006207:Half-Life; D006801:Humans; D007408:Intestinal Absorption; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics*; D058921:Purinergic P2Y Receptor Antagonists / Q000493:pharmacokinetics*; D000077486:Ticagrelor; D055815:Young Adult
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D051544:Cytochrome P-450 CYP3A; D000077486:Ticagrelor; D000241:Adenosine