Many patients take their medications with meals to minimize side effects and/or improve adherence to the administration schedule. This conventional strategy may be deleterious if an interaction occurs between the drug(s) and dietary substance(s). Currently, such interactions are largely unrecognized. Cranberry juice (CBJ), widely promoted for its health benefits, including prevention of urinary tract infections, is a common component of many popular juice-containing beverages. CBJ recently was reported to significantly increase the systemic exposure of the CYP3A substrate nifedipine in vivo in rats. CBJ inhibited the enteric (but not hepatic) CYP3A-mediated first-pass metabolism of nifedipine, an effect that mirrored that of grapefruit juice (GFJ). Preliminary data detailed in this application indicate that CBJ contains potent enteric CYP3A4 inhibitors. Clinically significant drug-GFJ interactions result from multiple furanocoumarins that inactivate enteric CYP3A4 permanently to elicit a prolonged inhibitory effect (~3 days). Cranberry is not a citrus fruit and is not known to contain furanocoumarins. Thus, CBJ likely contains unique CYP3A4 inhibitors with unknown mechanisms of action. Multiple independent laboratories have invested considerable time and resources in identifying the active ingredients responsible for drug-GFJ interactions. This slow, costly process was due in part to the lack of a multidisciplinary approach, combined with the lack of application of relevant in vitro systems. We hypothesize that a multidisciplinary translational research approach, which capitalizes on the combined expertise of drug metabolism scientists and natural products chemists, can rapidly identify the active CYP3A4 inhibitors in CBJ using well-characterized human intestine-derived in vitro systems. Identification of the major CYP3A4 inhibitors in CBJ would allow standardization of CBJs for patients at risk for drug-CBJ interactions, as well as provide marker compounds to identify other foods with interaction potential. Specifically, following (1) an evaluation of the effects of pretreatment of CBJ on the extent of enteric CYP3A4 inhibition in human volunteers, we will use human intestinal microsomes and CYP3A4-expressing Caco-2 cells to (2) identify potent CYP3A4 inhibitors in cranberry fractions and (3) define the concentration- and time-dependent inhibitory properties of the identified CYP3A4 inhibitors. Importantly, this novel experimental paradigm could be applied widely to identify additional natural compounds that alter drug disposition in humans in vivo. The long-term goal of the proposed translational research program is to further the mechanistic understanding of the effects of dietary substances on drug disposition. The knowledge gained will provide critical information to both clinicians and the lay public as to whether specific dietary substances can be taken safely with certain medications. ? ? ? ?
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