Drug interactions with dietary constituents are a concern for regulatory agencies, drug developers, clinicians, and patients. To date, much of the focus has been on grapefruit juice, which has been shown to inhibit enteric Cytochrome P450 (CYP) 3A and organic anion-transporting polypeptides. Consumption of blueberry juice and pomegranate juice has increased in recent years as the public has become more aware of the juices' putative health benefits. Unfortunately, no information is available regarding the effects of blueberry juice on drug disposition. Anecdotal case reports have suggested that pomegranate juice inhibits CYP2C9 activity; however, this potential interaction has not been examined in a controlled pharmacokinetic trial. In this work, we demonstrate that two brands of blueberry juice, both individually and as a 50:50 mixture, inhibit in vitro CYP3A and CYP2C9 activity with IC50 concentrations less than 3% (volume/volume). Additionally, pomegranate juice and pomegranate extract were found to reduce CYP2C9 activity in a concentration-dependent manner. The clinical relevance of the in vitro findings was then examined in three pharmacokinetic studies using healthy volunteers. As compared to the control condition, pretreatment with blueberry juice, pomegranate juice, or pomegranate extract did not impact the pharmacokinetics of the CYP2C9 probe substrate, flurbiprofen, or its principal metabolite, 4'-OH-flurbiprofen. In contrast, the positive control inhibitor, fluconazole, increased flurbiprofen AUC, Cmax, and t1/2, while decreasing the formation of 4'-OH-flurbiprofen. In the CYP3A interaction study, pretreatment with the 50:50 mixture of blueberry juices caused a small and statistically nonsignificant increase in the AUC for buspirone. A grapefruit juice low in furanocoumarins was still capable of inhibiting enteric CYP3A, and caused the AUC of buspirone to increase by approximately 100% over the control pretreatment value. Interestingly, individuals with high intrinsic CYP3A activity appeared to be more susceptible to increased buspirone exposure after consumption of both juices. Results of in vitro screening experiments suggested that the inhibitory effects observed for the fruit preparations were, at least in part, related to their flavonoid content, but not their anthocyanin or organic acid content. Collectively, our findings indicate that patients can consume blueberry juice and pomegranate preparations with CYP3A and CYP2C9 substrate drugs with minimal risk for pharmacokinetic drug interactions.
|Advisor:||Greenblatt, David J.|
|Commitee:||Akhlaghi, Fatemeh, Castellot, John, Court, Michael, Theoharides, Theoharis|
|School:||Sackler School of Graduate Biomedical Sciences (Tufts University)|
|Department:||Pharmacology & Experimental Therapeutics|
|School Location:||United States -- Massachusetts|
|Source:||DAI-B 74/05(E), Dissertation Abstracts International|
|Keywords:||Blueberry juice, Buspirone, Cytochrome P450, Drug interactions, Fruit juices, Pomegranate juice|
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