Potential Mechanisms of the Interaction
Several mechanisms of the interaction between cranberry juice and warfarin have been postulated. One potential mechanism involves salicylic acid, a constituent of many fruits and vegetables, including cranberries. Diets consisting of primarily vegetarian sources significantly increased serum and urinary concentrations of salicylates, often overlapping (at the lower end of the confidence interval) with concentrations measured in patients taking aspirin 75 mg/day. In addition, the amount of salicylic acid found in cranberry juice is 7 mg/L, and consuming 750 ml/day for 2 weeks can significantly increase the serum concentration to a mean of 0.34 μM/L. By comparison, the serum concentration of salicylic acid in patients taking aspirin 75 mg/day can range from 0.23-25.40 μM/L.
Although this explanation is based on the argument that salicylic acid exerts an antiplatelet effect that can increase bleeding risk, it does not account for the increase in the INR because alterations in platelet function do not affect the INR. The determination of INR is based on the prothrombin time, which reflects the activity of fibrinogen and vitamin K-dependent clotting factors II, VII, and X. The three published case reports[3,4,5] described substantial fluctuations in INR in addition to bleeding. Furthermore, unlike aspirin, which extensively inhibits platelet aggregation by means of irreversible acetylation of platelet cyclooxygenase-1 (COX-1), salicylic acid does not significantly reduce platelet function.[22,23,24] Although salicylates may increase the risk of gastrointestinal bleeding by reversibly inhibiting COX-1 in the gastric mucosa, they cannot irreversibly acetylate COX-1 and, therefore, are unlikely to induce the systemic bleeding risk described in the three reports.
Another possible explanation for the increased INR may stem from the increased salicylic acid concentration, which is highly protein bound, causing a displacement of warfarin from albumin-binding sites. Salicylic acid is usually 50-80% bound to plasma proteins but may exhibit high (90%) protein binding at low or therapeutic serum concentrations. Toxic levels are associated with 76% protein binding and high free levels.[25,26] Therefore, the salicylic acid content in cranberry juice leads to low serum levels of salicylic acid and a high percentage of protein binding.
Until recently, the most plausible explanation for the increase in INR in patients who take warfarin and drink cranberry juice involved flavonoids in cranberry extract. Flavonoids are phytochemicals with diverse chemical structures and a range of pharmacologic activities. These chemicals modify a variety of biochemical pathways to exert antimicrobial, antioxidant, analgesic, antitumorigenic, and estrogenic properties. In addition, certain flavonoids modulate the expression of specific cytochrome P450 (CYP) enzymes, inducing or inhibiting their activity.
Warfarin exists as a racemic mixture of the R- and S-enantiomers, with the S-enantiomer having 2-5 times more anticoagulant activity than the R-enantiomer. Biotransformation of the S-enantiomer to an inactive metabolite occurs predominantly by means of hydroxylation by CYP2C9, whereas the R-enantiomer involves CYP1A2 and CYP3A4. Inhibition of the CYP2C9 isoenzyme substantially increases the INR and potentiates the anticoagulant effect of warfarin. Several flavonoids, such as hyperforin and silibinin, inhibit the activity of CYP2C9.
Such alterations in metabolic processes have been well publicized, prompted by evidence that certain flavonoids in grapefruit juice can inhibit the activity of CYP3A4.[27,29] It had been postulated that flavonoids in cranberry juice may feasibly interfere with the enzymes responsible for metabolizing warfarin. However, a recent single-dose pharmacokinetic study in 12 healthy volunteers who drank 240 ml of cranberry juice reconstituted from frozen concentrate with a single 200-mg dose of cyclosporine failed to show significant influences on the disposition of cyclosporine, a CYP3A and P-glycoprotein substrate. In addition, a recent randomized five-way crossover study of healthy volunteers given single doses of flurbiprofen (as a surrogate index of CYP2C9 activity) after receiving 8 ounces of cranberry juice reconstituted from concentrate failed to show a significant reduction in flurbiprofen clearance or elimination half-life, suggesting that a pharmacokinetic interaction with warfarin by this mechanism was unlikely. Whereas neither of these studies defend a pharmacokinetic mechanism for this interaction, much smaller quantities of cranberry juice were consumed in these trials than what has been documented in the case reports and, therefore, do not rule out a dose-dependent alteration in the pharmacokinetics. A well-documented mechanism describing the interaction between warfarin and cranberry juice remains elusive.
Pharmacotherapy. 2006;26(9):1314-1319. © 2006 Pharmacotherapy Publications
Cite this: Interaction Between Warfarin and Cranberry Juice - Medscape - Sep 01, 2006.