A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Grapefruit juice markedly increases the plasma concentrations and antiplatelet effects of ticagrelor in healthy subjects
Tekijät: Holmberg MT, Tornio A, Joutsi-Korhonen L, Neuvonen M, Neuvonen PJ, Lassila R, Niemi M, Backman JT
Kustantaja: WILEY-BLACKWELL
Julkaisuvuosi: 2013
Journal: British Journal of Clinical Pharmacology
Tietokannassa oleva lehden nimi: BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
Lehden akronyymi: BRIT J CLIN PHARMACO
Vuosikerta: 75
Numero: 6
Aloitussivu: 1488
Lopetussivu: 1496
Sivujen määrä: 9
ISSN: 0306-5251
DOI: https://doi.org/10.1111/bcp.12026
Tiivistelmä
Aim 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 200ml of grapefruit juice or water thrice daily for 4 days. On day 3, they ingested a single 90mg 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 concentrationtime curve (AUC(0,)) to 221% of control (95% confidence interval 200, 245%). The Cmax and AUC(0,34h) (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 7.2h (P = 0.036). In good correlation with the elevated plasma ticagrelor concentrations, grapefruit juice enhanced the antiplatelet effect of ticagrelor, assessed with VerifyNow (R) and Multiplate (R) 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 juiceticagrelor interaction seems clinically important and indicates the significance of intestinal metabolism to ticagrelor pharmacokinetics.
Aim 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 200ml of grapefruit juice or water thrice daily for 4 days. On day 3, they ingested a single 90mg 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 concentrationtime curve (AUC(0,)) to 221% of control (95% confidence interval 200, 245%). The Cmax and AUC(0,34h) (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 7.2h (P = 0.036). In good correlation with the elevated plasma ticagrelor concentrations, grapefruit juice enhanced the antiplatelet effect of ticagrelor, assessed with VerifyNow (R) and Multiplate (R) 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 juiceticagrelor interaction seems clinically important and indicates the significance of intestinal metabolism to ticagrelor pharmacokinetics.
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