Abstract
Cranberry is a dietary supplement popularly used for the prophylaxis of urinary tract infection. Interestingly, cranberry–warfarin interactions in clinical reports have shown bidirectional outcomes. (±) Warfarin, a widely prescribed anticoagulant, but with a narrow therapeutic index, contains equal amounts of S- and R-warfarin, of which S-warfarin is more active. The aim of this study was to investigate the effects of different ingestion times of cranberry on the pharmacokinetics and pharmacodynamics of warfarin. Rats were orally administered (±) warfarin (0.2 mg/kg) with and without cranberry (5.0 g/kg) at 0.5 h prior to the warfarin, and at 10 h after the warfarin. The plasma concentrations of S- and R-warfarin were determined by LC/MS. The results indicate that cranberry ingested at 0.5 h before (±) warfarin significantly decreased the systemic exposures of S-warfarin and R-warfarin. Conversely, when cranberry was ingested at 10 h after (±) warfarin, the elimination of S-warfarin was significantly inhibited, and the anticoagulation effect of (±) warfarin was significantly enhanced. The results of the mechanism studies indicate that cranberry activated the breast cancer resistance protein (BCRP), which mediated the efflux transports of S-warfarin and R-warfarin. Moreover, the metabolites of cranberry inhibited cytochrome P450 (CYP) 2C9, the main metabolizing enzyme for S-warfarin. In conclusion, cranberry affected the pharmacokinetics of (±) warfarin in a bidirectional manner by activating the BCRP by CJ during absorption and inhibiting the BCRP and CYP2C9 by CMs during elimination, depending on the ingestion time of CJ. The combined use of cranberry with warfarin should be avoided.
Highlights
Introduction published maps and institutional affilCranberry is the fruit of Vaccinium microcarpum, V. oxycoccos, or V. erythrocarpum (Ericaceae)
The results show that Cranberry Juice (CJ) ingestion at 0.5 h before (±) warfarin significantly decreased the Cmax and AUC0-t of S-warfarin by 48% and 34%, and reduced the Cmax and AUC0–t of R-warfarin by 51% and 52%, respectively
The results revealed that Cranberry Metabolites (CMs) at full, one half, and one quarter of the serum concentrations significantly decreased the activity of CYP1A2 by 25%, 20%, and 14%, respectively, when compared to those of corresponding concentrations of blank serum
Summary
Introduction published maps and institutional affilCranberry is the fruit of Vaccinium microcarpum, V. oxycoccos, or V. erythrocarpum (Ericaceae). Cranberry-based supplements have been popularly used for the prophylaxis of urinary tract infections, especially for the elderly [1]. According to a market report, cranberry is the third top-selling supplement [2]. Cranberry contains a variety of polyphenols, including proanthocyanidins, anthocyanins, flavonoids, and phenolic acids, which exhibit numerous beneficial effects, such as the prevention of microbial infections, cardiovascular diseases, and cancers, and the improvement of lipid profiles and digestive disorders [1]. (±) Warfarin, a vitamin K antagonist, is a widely prescribed oral anticoagulant for the prevention and treatment of thromboembolic disorders and recurrent transient ischemic attacks, as well as for reducing the risk of recurrent myocardial infarction [3]. Being acidic (pKa = 4.94), (±) warfarin exists as anions in the body.
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