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% (p0.001), and had no effect on geometric mean terminal half-life, indicating inhibition of enteric, but not hepatic, CYP3A-mediated first-pass metabolism of midazolam. This approach both showed a potential drug interaction liability with cranberry juice and substantiated that rigorous in vitro characterization of dietary substances is required before initiation of clinical drug-diet interaction studies.

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 0.05), from 20% to >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).

OBJECTIVES: Recent anecdotal, unvalidated case reports have suggested potentiation of warfarin-induced anticoagulation by cranberry juice, possibly through inhibition of human cytochrome P450 (CYP) 2C9, the enzyme responsible for the clearance of the active S-enantiomer of warfarin. To address this question, the effect of cranberry juice and other beverages on CYP2C9 activity was evaluated in vitro and in vivo.

METHODS: The effects of 4 beverages on CYP2C9 activity were studied in human liver microsomes, by use of flurbiprofen hydroxylation as the index reaction. In a clinical study 14 healthy volunteers received 100 mg flurbiprofen on 5 occasions in a crossover fashion, with at least 1 week separating the 5 trials. Flurbiprofen was preceded in random sequence by the following: (1) cranberry juice placebo (8 oz), (2) cranberry juice (8 oz), (3) brewed tea (8 oz), (4) grape juice (8 oz), and (5) fluconazole, a CYP2C9 inhibitor serving as a positive control, with 8 oz of water.

RESULTS: Flubiprofen hydroxylation in vitro was reduced to 11% +/- 8% of control by 2.5% (vol/vol) brewed tea, to 10% +/- 7% of control by grape juice, to 56% +/- 16% of control by cranberry juice, to 85% +/- 5% of control by cranberry juice placebo, and to 21% +/- 6% of control by the index inhibitor sulfaphenazole (2.5 micromol/L) (P .01 for all comparisons versus control). Flurbiprofen clearance (29-33 mL/min) and elimination half-life (3.3-3.4 hours) did not differ significantly among trials 1, 2, 3, and 4. However, clearance in the fluconazole treatment condition (trial 5) was significantly reduced compared with the placebo control (17 +/- 5 mL/min versus 31 +/- 8 mL/min, P .05), and the half-life was prolonged (5.3 +/- 1.6 hours versus 3.3 +/- 0.8 hours, P .05). Formation of 4-hydroxyflurbiprofen was correspondingly reduced by fluconazole (P .05).

CONCLUSIONS: Although grape juice and tea impaired CYP2C9 activity in vitro, none of the 3 beverages altered CYP2C9-mediated clearance of flurbiprofen in humans, making a pharmacokinetic interaction with warfarin highly unlikely.

The question of potentiation of warfarin anticoagulation by cranberry juice (CJ) is a topic of biomedical importance. Anecdotal reports of CJ-warfarin interaction are largely unconfirmed in controlled studies. Thirty patients on stable warfarin anticoagulation (international normalized ratio [INR], 1.7-3.3) were randomized to receive 240 mL of CJ or 240 mL of placebo beverage, matched for color and taste, once daily for 2 weeks. The INR values and plasma levels of R- and S-warfarin were measured during the 2-week period and a 1-week follow-up period. The CJ and placebo groups (n=14 and 16, respectively) did not differ significantly in mean plasma R- and S-warfarin concentrations. Eight patients (4 on CJ, 4 on placebo) developed minimally elevated INR (range, 3.38-4.52) during the treatment period. Mean INR differed significantly (P.02) only on treatment day 12; at all other time points, the groups did not differ. Cranberry juice has no effect on plasma S- or R-warfarin plasma levels, excluding a pharmacokinetic interaction. A small though statistically significant pharmacodynamic enhancement of INR by CJ at a single time point is unlikely to be clinically important and may be a random change. Enhanced warfarin anticoagulation attributed to CJ in anecdotal reports may represent a chance temporal association.

Cranberry juice consumption is often recommended along with low-dose oral antibiotics for prophylaxis for
recurrent urinary tract infection (UTI). Because multiple membrane transporters are involved in the intestinal
absorption and renal excretion of -lactam antibiotics, we evaluated the potential risk of pharmacokinetic
interactions between cranberry juice and the -lactams amoxicillin (amoxicilline) and cefaclor. The amoxicillin-
cranberry juice interaction was investigated in 18 healthy women who received on four separate occasions
a single oral test dose of amoxicillin at 500 mg and 2 g with or without cranberry juice cocktail (8 oz) according
to a crossover design. A parallel cefaclor-cranberry juice interaction study was also conducted in which 500 mg
cefaclor was administered with or without cranberry juice cocktail (12 oz). Data were analyzed by noncompartmental
methods and nonlinear mixed-effects compartmental modeling. We conclude that the concurrent
use of cranberry juice has no significant effect on the extent of oral absorption or the renal clearance of
amoxicillin and cefaclor. However, delays in the absorption of amoxicillin and cefaclor were observed. These
results suggest that the use of cranberry juice at usual quantities as prophylaxis for UTI is not likely to alter
the pharmacokinetics of these two oral antibiotics.