Grapefruit juice markedly increases the plasma concentrations and antiplatelet effects of ticagrelor in healthy subjects
Article first published online: 20 MAY 2013
© 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society
British Journal of Clinical Pharmacology
Volume 75, Issue 6, pages 1488–1496, June 2013
How to Cite
Holmberg, M. T., Tornio, A., Joutsi-Korhonen, L., Neuvonen, M., Neuvonen, P. J., Lassila, R., Niemi, M. and Backman, J. T. (2013), Grapefruit juice markedly increases the plasma concentrations and antiplatelet effects of ticagrelor in healthy subjects. British Journal of Clinical Pharmacology, 75: 1488–1496. doi: 10.1111/bcp.12026
- Issue published online: 20 MAY 2013
- Article first published online: 20 MAY 2013
- Accepted manuscript online: 6 NOV 2012 04:34AM EST
- Manuscript Accepted: 31 OCT 2012
- Manuscript Received: 29 SEP 2012
- Helsinki University Central Hospital Research Fund
- Sigrid Jusélius Foundation (Helsinki, Finland)
- drug interaction;
- grapefruit juice;
This study examined the effects of grapefruit juice on the new P2Y12 inhibitor ticagrelor, which is a substrate of CYP3A4 and P-glycoprotein.
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.
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.
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.