Inhibition of Cytochrome P450 Enzymes by Fruit Juices: In Vitro Effects, Clinical Relevance, and Therapeutic Implications.
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 ... read morepublic 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
Thesis (Ph.D.)--Tufts University, 2012.
Submitted to the Dept. of Pharmacology & Experimental Therapeutics.
Advisor: David Greenblatt.
Committee: Michael Court, John Castellot, Theoharis Theoharides, and Fatemeh Akhlaghi.
Keyword: Pharmacology.read less