Grapefruit juice inhibits the metabolic activation of clopidogrel.
Cytochrome P450 (CYP) enzymes, including CYP2C19 and CYP3A4, participate in the bioactivation of clopidogrel. Grapefruit juice constituents potently inactivate intestinal CYP3A4 and have been shown to inhibit CYP2C19 as well. In a randomized crossover study, 14 healthy volunteers ingested 200 ml of grapefruit juice or water three times daily for 3 days. On day 3, they ingested a single 600-mg dose of clopidogrel. Grapefruit juice reduced the peak plasma concentration (Cmax) of the active metabolite of clopidogrel to 13% of the control (range 11-17%, P < 0.001) and the area under the plasma concentration-time curve from 0 to 3 h to 14% (range 12-17%, P < 0.001) of the control, but it had no significant effect on the parent clopidogrel. Moreover, grapefruit juice markedly decreased the platelet-inhibitory effect of clopidogrel, as assessed with the VerifyNow P2Y12 test in two of the participants. In conclusion, concomitant use of grapefruit juice may impair the efficacy of clopidogrel. Therefore, the use of grapefruit juice is best avoided during clopidogrel therapy.
Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital, Helsinki, Finland.
M T
MT
Holmberg
Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital, Helsinki, Finland.
A
A
Tornio
Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital, Helsinki, Finland.
M
M
Neuvonen
Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital, Helsinki, Finland.
P J
PJ
Neuvonen
Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital, Helsinki, Finland.
J T
JT
Backman
Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital, Helsinki, Finland.
M
M
Niemi
D000328:Adult; D019540:Area Under Curve; D001628:Beverages / Q000009:adverse effects*; D001711:Biotransformation / Q000187:drug effects*; D032083:Citrus paradisi / Q000009:adverse effects*; D000077144:Clopidogrel; D016001:Confidence Intervals; D018592:Cross-Over Studies; D005260:Female; D018565:Food-Drug Interactions; D005838:Genotype; D006207:Half-Life; D006801:Humans; D008297:Male; D010975:Platelet Aggregation Inhibitors / Q000378:metabolism*; D010979:Platelet Function Tests; D058925:Receptors, Purinergic P2Y12 / Q000235:genetics; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000378:metabolism; D055815:Young Adult
D010975:Platelet Aggregation Inhibitors; D058925:Receptors, Purinergic P2Y12; D000077144:Clopidogrel; D013988:Ticlopidine