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Grant Abstract

Grant Number: 5R21AT002073-02
Project Title: Drug Interactions and Bioavailability of Cranberry

Abstract: DESCRIPTION (provided by applicant): Cranberry (CB) juice and powders are currently being used as complementary and alternative medications. CB products may be used alone or in combination with conventional medications to treat urinary tract infection, or other medications to treat acute or chronic conditions. CB is a rich source of flavonoids, a class of phytochemicals with diverse biological activities. The specific aims of this research are 1) to evaluate the potential for CB-drug interactions and 2) to determine the pharmacokinetics and renal clearance of four major CB flavonoids. A normal volunteer study is proposed to determine the potential of CB to participate in interactions with conventional drugs. The induction/inhibition of the major cytochrome P-450 (CYP) enzymes will be the primary method of evaluation. The CYP isoforms to be studied, CYP3A4, CYP2D6 and CYP1A2, are involved in the metabolism of >80% of marketed prescription and over the counter medications. Single doses of the three safe, probe drugs alprazolam (ALPZ; 3A4 probe), dextromethorphan (DM; CYP2D6 probe), and caffeine (CAF; CYP1A2 probe) will be administered at baseline (before treatment with CB) and after a 14-day treatment period with CB powder. Changes in the pharmacokinetics of these probe drugs will indicate the degree of specific enzyme inhibition or induction. In the same normal volunteers, the key pharmacokinetic parameters for four major CB flavonoids will be estimated by following the plasma concentration versus time course of absorbed flavonoids and their excretion in urine. The area under the plasma concentration versus time curve (AUC), oral clearance (Clo), terminal elimination half-life (T1/2) and renal clearance (Clren) will be determined for: epicatechin, quercetin (total glycosides), procyanidin A2, and cyanidin-3-galactoside. These components represent the major classes of flavonoids in CB and are selected for study due to their abundance in CB and their documented biological activities. The pharmacokinetics and renal clearance of CB flavonoids will be determined first after a single dose of a characterized CB juice prior to administration of any probe drugs. Steady-state plasma levels of flavonoids will be determined at the end of the 14-day treatment period of multiple dosing with the characterized CB powder. This research will provide new, important data on the pharmacokinetics of flavonoids from CB juice and from a CB powder, an area where no data currently exist. This information is essential to elucidate the mechanisms of action of CB flavonoids in the context of specific conditions/diseases and to evaluate CB as a source of dietary flavonoids. These data will also complement NCCAM studies assessing the clinical safety and efficacy of CB and will allow more informed recommendations about the use of CB when combined with conventional medications.

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