Interaction of flurbiprofen with cranberry juice, grape juice, tea, and fluconazole: In vitro and clinical studies

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 μmol/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. Clinical Pharmacology & Therapeutics (2006) 79, 125–133; doi: 10.1016/j.clpt.2005.09.014