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Abstract
Grant Number: 5R21AT002077-02 Project Title: Cranberry: Interactions with Anti-infectious Agents
PI Information: Name Title ANDERSON, GAIL D. galia@u.washington.edu PROFESSOR OF PHARMACY Abstract: DESCRIPTION (provided by applicant): Gaining a better understanding of interactions between antibiotics and cranberry juice is of critical importance to a patients with urinary tract infections (UTI). With annual 7 to 8 million office visits for UTIs, addressing this interaction is also of public health concern. Men are less prone to UTIs than women; 20% of women have at least one UTI and a substantial portion have recurrent UTIs. Similarly, children are afflicted with UTIs, albeit at a lower frequency but with the added risk of pyelonephritis and chronic renal dysfunction with undertreatment. The bacterial pathogens in UTI are typically responsive to trimethoprim-sulfamethoxazole, quinolones, and the beta-lactams (penicillins, cephalosporins). The cephalosporin antibiotics are especially useful in the cases of resistance to amoxicillin and trimethoprim-sulfamethoxazole and treatment of chronic or recurrent infections. Cranberry juice is widely used to prevent and treat UTI in spite of limited evidence of efficacy. Recent studies have shown that other fruit juices (i.e., grapefruit, orange and apple juice) can alter the bioavailability of drugs. Grapefruit juice inhibits intestinal CYP 3A, significantly increasing the plasma concentrations of drugs that undergo extensive pre-systemic CYP 3A metabolism. The furanocoumarins and bioflavonoids, which are present in these juices and cranberry juice, inhibit intestinal OATP activity and co-administration of grapefruit, orange or apple juice significantly reduced the oral absorption of the OATP substrate fexofenadine, which is a commonly used antihistamine. These findings represent the first example of food-drug interactions involving altered activity of epithelial (i.e., intestinal) drug transporter function. The intestinal absorption of many beta-lactam antibiotics is mediated by peptide transporters (e.g. PepT1) and possibly OATP. Moreover, the renal clearance of several penicillin and cephalosporins involves proximal tubular secretion, which is governed by organic anion transporters (viz. OATs) and peptide transporters (viz. PepT2) at the basolateral and apical membranes of the tubular epithelium, respectively. Since cranberry juice contained bioflavonoids as in the citrus juices and a high content of organic acids (e.g. benzoic acid), we hypothesize that cranberry juice has the potential to modulate the absorption and renal excretion of many beta-lactam antibiotics. This altered transport could lower the urinary concentrations of select beta-lactam antibiotics and the effectiveness of the antibiotic in treating the UTI. The proposed studies are designed to first, determine whether concurrent cranberry juice administration lowers the urinary concentrations of two commonly used beta-lactam antibiotics, amoxicillin and cefaclor, in children. Secondly, to conduct a rigorous study on amoxicillin pharmacokinetics in adult healthy women that will separate the actions of cranberry juice on intestinal absorption and renal clearance of this prototype beta-lactam antibiotic. The in vivo pharmacokinetic studies will be accompanied by a comprehensive series of experiments in vitro that should reveal the precise effects of cranberry juice and its ingredients and metabolites on the individual transporters of concern.
Public Health Relevance:
This Public Health Relevance is not available.Thesaurus Terms:
diet therapy, flavonoid, fruit, gastrointestinal drug absorption, nutrient drug interaction, pharmacokinetics, urinary tract infection
cephalosporin, clearance rate, membrane transport protein, penicillin
CHO cell, adolescence (12-20), alternative medicine, clinical research, female, human subject, middle childhood (6-11), nutrition related tag, patient oriented research
Institution: UNIVERSITY OF WASHINGTON Office of Sponsored Programs SEATTLE, WA 981959472 Fiscal Year: 2005 Department: PHARMACY Project Start: 06-JAN-2004 Project End: 31-DEC-2007 ICD: NATIONAL CENTER FOR COMPLEMENTARY & ALTERNATIVE MEDICINE IRG: ZAT1