Case reports suggest that cranberry juice can increase the anticoagulant effect of warfarin. We investigated the effects of cranberry juice on R-S-warfarin, tizanidine, and midazolam; probes of CYP2C9, CYP1A2, and CYP3A4. Ten healthy volunteers took 200 ml cranberry juice or water t.i.d. for 10 days. On day 5, they ingested 10 mg racemic R-S-warfarin, 1 mg tizanidine, and 0.5 mg midazolam, with juice or water, followed by monitoring of drug concentrations and thromboplastin time. Cranberry juice did not increase the peak plasma concentration or area under concentration-time curve (AUC) of the probe drugs or their metabolites, but slightly decreased (7%; P=0.051) the AUC of S-warfarin. Cranberry juice did not change the anticoagulant effect of warfarin. Daily ingestion of cranberry juice does not inhibit the activities of CYP2C9, CYP1A2, or CYP3A4. A pharmacokinetic mechanism for the cranberry juice-warfarin interaction seems unlikely.

BACKGROUND AND PURPOSE: Patients commonly take complementary medicines in conjunction with warfarin yet evidence supporting the safety or the risk of a herb-drug interaction is lacking. The aim of this study was to investigate the possible impact of two commonly used herbal medicines, garlic and cranberry, on the pharmacokinetics and pharmacodynamics of warfarin in healthy male subjects.

EXPERIMENTAL APPROACH: An open-label, three-treatment, randomized crossover clinical trial was undertaken and involved 12 healthy male subjects of known CYP2C9 and VKORC1 genotype. A single dose of 25 mg warfarin was administered alone or after 2 weeks of pretreatment with either garlic or cranberry. Warfarin enantiomer concentrations, INR, platelet aggregation and clotting factor activity were measured to assess pharmacokinetic and pharmacodynamic interactions between warfarin and herbal medicines.

KEY RESULTS: Cranberry significantly increased the area under the INR-time curve by 30% when administered with warfarin compared with treatment with warfarin alone. Cranberry did not alter S- or R-warfarin pharmacokinetics or plasma protein binding. Co-administration of garlic did not significantly alter warfarin pharmacokinetics or pharmacodynamics. Both herbal medicines showed some evidence of VKORC1 (not CYP2C9) genotype-dependent interactions with warfarin, which is worthy of further investigation.

CONCLUSIONS AND IMPLICATIONS: Cranberry alters the pharmacodynamics of warfarin with the potential to increase its effects significantly. Co-administration of warfarin and cranberry requires careful monitoring.

Research suggests that anthocyanins from berry fruit may affect a variety of physiological responses, including endothelial function, but little information is available regarding the pharmacokinetics of these flavonoids in humans. To determine the pharmacokinetics of cranberry anthocyanins, a study was undertaken in 15 participants (age: 62 +/- 8 y) with coronary artery disease. Blood and urine samples were collected between baseline (0 h) and 4 h after consumption of 480 mL cranberry juice (54% juice; 835 mg total polyphenols; 94.47 mg anthocyanins). Marked inter-individual differences in plasma anthocyanin pharmacokinetics were observed with maximum anthocyanin concentrations detected between 1 and 3 h. Cranberry anthocyanins were bioavailable but with notable differences in the maximum concentration and area under the curve(0-4h) between individual participants. The pattern of anthocyanin glucosides observed in plasma and urine generally reflected the relative concentration determined in the juice. Plasma concentrations of the individual anthocyanins ranged between 0.56 and 4.64 nmol/L. Total recovery of urinary anthocyanin was 0.79 +/- 0.90% of the dose delivered. These data are in agreement with the pharmacokinetics of anthocyanins from other foods suggesting that cranberry anthocyanins are poorly absorbed and rapidly removed from plasma. Observed concentrations of plasma anthocyanins appear insufficient to alter radical load or redox potential but may be adequate to affect signal transduction and/or gene expression.

PURPOSE: The interaction potential between warfarin and cranberry juice is discussed.

SUMMARY: Reports from the United Kingdom have raised concern over the interaction potential between cranberry juice and warfarin. Warfarin is the most commonly prescribed oral medication for anticoagulation therapy. Cranberry juice is a flavonoid, which has been shown to induce, inhibit, or act as a substrate for the biosynthesis of several cytochrome P-450 (CYP) isoenzymes. Specifically, cranberry juice may inhibit the activity of CYP2C9, the primary isoenzyme involved in the metabolism of S-warfarin. A search of the medical literature identified three peer-reviewed case reports and two peer-reviewed, prospective, randomized, placebo-controlled clinical trials using metabolic surrogates of warfarin (flurbiprofen and cyclosporine) that described possible interactions between cranberry juice and warfarin. Two case reports suggested that cranberry juice increased the International Normalized Ratio (INR) of patients taking warfarin, but neither clearly identified cranberry juice as the sole cause of INR elevation. One case report appeared to show a correlation between the effects of cranberry juice and warfarin metabolism. Both clinical trials indicated the lack of an interaction between cranberry juice and CYP isoenzymes 2C9 and 3A, both of which are necessary in warfarin metabolism. More studies are required to determine the potential interaction between cranberry juice and warfarin.

CONCLUSION: The available data do not seem to show a clinically relevant interaction between cranberry juice and warfarin; however, patients taking warfarin with cranberry juice should be cautioned about the potential interaction and monitored closely for INR changes and signs and symptoms of bleeding.

SUBJECT: Case reports suggest an association between cranberry juice and potentiation of warfarin. Studies using 240 ml of cranberry juice daily demonstrated no interaction. It is unknown if higher amounts of cranberry juice will interact with warfarin.

WHAT THIS STUDY ADDS: Cranberry juice at 240 ml twice daily does not alter the pharmacodynamics of warfarin.

AIM: To determine if high-dose cranberry juice (240 ml twice daily) alters the pharmacodynamic action of warfarin.

METHODS: Ten male patients taking stable doses of warfarin were given cranberry juice at 240 ml twice daily for 7 days. Prothrombin times were drawn at baseline and days 2, 6 and 8 after administration of the juice. Prothrombin times were averaged for each day and mean times were compared from each study day to baseline using repeated measures ANOVA.

RESULTS: There was no statistical difference between mean prothrombin time at baseline and any day tested during juice administration.

CONCLUSIONS: Cranberry juice (240 ml twice daily for 1 week) did not alter the pharmacodynamics of warfarin in patients.

Little information is available about drug interactions with cranberry juice (CJ). Using microsomes from the human liver and rat small intestine, this study was designed to determine whether CJ could inhibit CYP3A-mediated nifedipine (NFP) oxidase activity; it showed that CJ was a potent inhibitor of human and rat CYP3A. Preincubation with 10% vol/vol of CJ and 1 mM NADPH for 10 min resulted in significant inhibition of the NFP oxidation activity of human and rat CYP3A (18.2 and 12.6% decreases, respectively, compared with preincubation experiments without NADPH). In addition, the pharmacokinetic interaction between CJ and NFP in vivo was confirmed in rats. In comparison with a control group, the area under the concentration-time curve (AUC) of NFP was approximately 1.6-fold higher when CJ (2 mL) was injected intraduodenally 30 min before the intraduodenal administration of NFP (30 mg kg(-1)). However, the mean residence time, the volume of distribution and the elimination rate constant were not changed significantly. These data suggest that CJ component(s) inhibit the function of enteric CYP3A. In conclusion, it was found that CJ inhibits the CYP3A-mediated metabolism of NFP in both rats and humans. Furthermore, CJ alters NFP pharmacokinetics in rats.

Emerging epidemiological evidence is increasingly pointing to the beneficial effects of fruits and vegetables in managing chronic and infectious diseases. These beneficial effects are now suggested to be due to the constituent phenolic phytochemicals having antioxidant activity. Cranberry like other fruits is also rich in phenolic phytochemicals such as phenolic acids, flavonoids and ellagic acid. Consumption of cranberry has been historically been linked to lower incidences of urinary tract infections and has now been shown to have a capacity to inhibit peptic ulcer-associated bacterium, Helicobacter pylori. Isolated compounds from cranberry have also been shown to reduce the risk of cardiovascular diseases. Recent evidence suggests the ability of phytochemical components in whole foods in being more effective in protectively supporting human health than compared to isolated individual phenolic phytochemicals. This implies that the profile of phenolic phytochemicals determines the functionality of the whole food as a result of synergistic interaction of constituent phenolic phytochemicals. Solid state bioprocessing using food grade fungi common in Asian food cultures as well as cranberry phenolic synergies through the addition of functional biphenyls such as ellagic acid and rosmarinic acid along with processed fruit extracts have helped to advance these concepts. These strategies could be further explored to enrich cranberry and cranberry products with functional phytochemicals and further improve their functionality for enhancing health benefits.

AIM: To investigate a potential interaction between cranberry juice and diclofenac, a substrate of CYP2C9.

METHODS: The inhibitory effect of cranberry juice on diclofenac metabolism was determined using human liver microsome assay. Subsequently, we performed a clinical trial in healthy human subjects to determine whether the repeated consumption of cranberry juice changed the diclofenac pharmacokinetics.

RESULTS: Cranberry juice significantly suppressed diclofenac metabolism by human liver microsomes. On the other hand, repeated consumption of cranberry juice did not influence the diclofenac pharmacokinetics in human subjects.

CONCLUSIONS: Cranberry juice inhibited diclofenac metabolism by human liver microsomes, but not in human subjects. Based on the present and previous findings, we think that although cranberry juice inhibits CYP2C9 activity in vitro, it does not change the pharmacokinetics of medications metabolized by CYP2C9 in clinical situations.

An in vivo study in rats showed a cranberry juice product to inhibit the intestinal first-pass metabolism of the CYP3A substrate nifedipine. However, a clinical study involving the CYP3A probe substrate midazolam and a different cranberry juice product showed no interaction. Because the composition of bioactive components in natural products can vary substantially, a systematic in vitro-in vivo approach was taken to identify a cranberry juice capable of inhibiting enteric CYP3A in humans. First, the effects of five cranberry juices, coded A through E, were evaluated on midazolam 1'-hydroxylation activity in human intestinal microsomes. Juice E was the most potent, ablating activity at 0.5% juice (v/v) relative to control. Second, juice E was fractionated to generate hexane-, chloroform-, butanol-, and aqueous-soluble fractions. The hexane- and chloroform-soluble fractions at 50 microg/ml were the most potent, inhibiting by 77 and 63%, respectively, suggesting that the CYP3A inhibitors reside largely in these more lipophilic fractions. Finally, juice E was evaluated on the oral pharmacokinetics of midazolam in 16 healthy volunteers. Relative to water, juice E significantly increased the geometric mean area under the curve (AUC)(0-infinity) of midazolam by approximately 30% (p=0.001), decreased the geometric mean 1'-hydroxymidazolam/midazolam AUC(0-infinity) ratio by approximately 40% (p

BACKGROUND: Cranberry products have been implicated in several case reports to enhance the anticoagulant effect of warfarin. The mechanism could involve inhibition of the hepatic CYP2C9-mediated metabolic clearance of warfarin by components in cranberry. Because dietary/natural substances vary substantially in bioactive ingredient composition, multiple cranberry products were evaluated in vitro before testing this hypothesis in vivo.

METHODS: The inhibitory effects of five types of cranberry juices were compared with those of water on CYP2C9 activity (S-warfarin 7-hydroxylation) in human liver microsomes (HLM). The most potent juice was compared with water on S/R-warfarin pharmacokinetics in 16 healthy participants given a single dose of warfarin 10 mg.

RESULTS: Only one juice inhibited S-warfarin 7-hydroxylation in HLM in a concentration-dependent manner (P 95% at 0.05% to 0.5% juice (v/v), respectively. However, this juice had no effect on the geometric mean AUC(0-∞) and terminal half-life of S/R-warfarin in human subjects.

CONCLUSIONS: A cranberry juice that inhibited warfarin metabolism in HLM had no effect on warfarin clearance in healthy participants. The lack of an in vitro-in vivo concordance likely reflects the fact that the site of warfarin metabolism (liver) is remote from the site of exposure to the inhibitory components in the cranberry juice (intestine).