Drug Interactions and Bioavailability of Cranberry

The use of cranberry (CB) juice and powders, both alone and in combination with conventional
medicine, has become more common for the treatment of urinary tract infections (UTIs) and and
other acute or chronic conditions. Cytochromes P450 enzymes are a group of proteins involved
in metabolism of certain substances. A group of cytochrome P-450 (CYP) enzymes are
extensively involved in drug metabolism. The pharmacokinetics of many drugs often vary
considerably among individuals, largely because of variations in the expression of different
cytochrome P-450 (CYP) enzymes in the liver and other tissues. Flavonoids are antioxidants
that may have health benefits. The flavonoids may also be responsible for cranberry's effects
on urinary tract infections.

To evaluate the drug interaction potential of cranberry, single doses of the three safe probe
drugs alprazolam, dextromethorphan, and caffeine will be administered before and after a
14-day treatment period with cranberry powder. Changes in the pharmacokinetics of these probe
drugs will indicate the degree of enzyme inhibition or induction. 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.

Inclusion Criteria:

- Females must have a negative urine pregnancy test prior to enrollment and must be
committed to using barrier methods of birth control throughout the study.

Exclusion Criteria:

- Clinically significant diseases or abnormal laboratory values as assessed during the
screening medical history, physical exam, and laboratory evaluations.

- A history (within the past year) or presence of clinically significant cardiovascular,
cerebrovascular, renal, hepatic, gastrointestinal, pulmonary, immunological,
hematological, endocrine, or neurologic disease. The exclusion criteria also includes
1) positive urine pregnancy test 2) The use of oral contraceptives 3) The lack of use
of acceptable barrier methods of birth control unless abstinent

- Use of any concomitant medication including herbal medications or a history of
hypersensitivity to the medications used in the study

- History of sensitivity to CB juice or products

- Poor metabolizers of CYP2D6

- Active smoking or use of caffeine-containing beverages for 2 weeks prior to and during
the study

- Inability to conform with dietary restrictions required for the study

- Drug or alcohol abuse (more than 3 drinks/day)