The warfarin–cranberry juice interaction revisited: A systematic in vitro–in vivo evaluation

Ngoc Ngo¹, Scott J Brantley¹, Daniel R Carrizosa², Angela DM Kashuba¹, E Claire Dees², David J Kroll³, Nicholas H Oberlies⁴, Mary F Paine<sup>1

1</sup>UNC Eshelman School of Pharmacy and ²Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; ³Biomanufacturing Research Institute and Technology Enterprise and the Department of Pharmaceutical Sciences, North Carolina Central University, Durham, NC, USA; ⁴Department of Chemistry and Biochemistry, The University of North Carolina at Greensboro, Greensboro, NC, USA

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 AUC0_0-oo 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).

Keywords: warfarin, cranberry, interaction, CYP2C9, metabolism, inhibition