Cranberry products have a long history of medical use because of their beneficial effects on human health and are promoted as complementary or alternative means of prophylaxis for UTIs (3
). Limited studies have evaluated the drug interaction potential of cranberry juice. Recent studies have shown that cranberry juice potently inhibits CYP3A and CYP2C9 in vitro (9
); however, in vivo studies with probe substrates for CYP2C9 (S
-warfarin), CYP1A2 (tizandine), and CYP3A4 (midazolam) have not demonstrated an interaction (20
). Despite the lack of an effect of cranberry juice on the pharmacokinetics of warfarin (20
), several case reports have indicated that cranberry juice results in an enhanced antithrombotic effect of warfarin (8
), suggesting a possible pharmacodynamic effect.
A number of studies have reported incidences of apple-, orange-, and grapefruit-drug interactions (6
). The potential effect of cranberry juice on drug transporters had not been investigated prior to our study. Given the involvement of drug transporters in the active intestinal absorption and renal excretion of the β-lactams, in the present study we examined the potential of their interaction with CJC in healthy women. Two antibiotics exhibiting different absorption characteristics were chosen for the studies. On the basis of the dose-dependent absorption, amoxicillin absorption is shown to be mediated by passive diffusion and active transport; while it is more hydrophilic, the intestinal absorption of cefaclor is mainly an active process (30
Following the concurrent consumption of CJC at 8 to 12 oz, the common doses used for UTI prophylaxis, we did not observe a significant difference in the amoxicillin and the cefaclor AUCs in the female subjects. Hence, regular-strength CJC at the quantity usually consumed has little effect on the extent of amoxicillin and cefaclor oral absorption. In view of our positive in vitro findings of hPepT1 inhibition by CJC, the negligible in vivo effect of juice may be explained by sufficient fluid dilution of the ingested juice in the gastrointestinal tract as well as the limited residence time of the inhibitory components of CJC in the small intestine. Both factors would reduce the extent and duration of CJC inhibition in vivo. In addition, the passive diffusion of amoxicillin across the intestinal epithelium is also likely to lower the magnitude of any transporter-based interaction. Even though CJC did not affect the extent of absorption, our noncompartmental model analysis suggested that these antibiotics have slower absorption rates in the presence of the juice. This was substantiated by our population pharmacokinetic analysis, which allowed us to fully model the changes in Cmax and Tmax following juice administration. Cranberry juice intake is predicted to lead to a notable increase in Tmax and a decrease in Cmax for both amoxicillin and cefaclor (Fig. and ). The underlying mechanism(s) of the absorption rate change is not known. It could be the result of a modest inhibition of hPepT1 by juice, which affects only the rate but not the extent of the absorption. We also cannot rule out the possibilities of other nonspecific effects of juice in the gut, such as an altered drug dissolution rate or ionization due to changes in gastric pH.
Renal tubular secretion serves as an efficient means of targeting antibiotics to the urinary tract for the treatment of infection. Factors affecting proximal tubular secretion, such as the suppression of OAT3- and PepT2-mediated transport, may have a direct impact on the efficacies of antibiotics for the treatment of UTIs. As shown by our results, CJC at 8 to 12 oz did not elicit significant interference with the CLR of amoxicillin and cefaclor. The lack of a systemic effect of juice may reflect the low circulating concentrations of inhibitory juice constituents and its metabolite(s) following the intake of CJC.
Like amoxicillin and cefaclor, other β-lactams, such as cefixime and cefadroxil, exhibit similar disposition pathways, including PepT1-mediated active absorption in the intestine as well as active renal tubular transport in the kidneys. Our results suggest that these other β-lactams may also be safely coadministered with cranberry juice at the usual daily amounts for the prophylaxis of UTI without significant pharmacokinetic interactions. Nonetheless, as the effect of juice could be variable, depending on the specific pharmacokinetic properties of the antibiotics, along with administration-related factors, such as the concentration and volume of the juice ingested, we cannot entirely exclude the potential risk of an antibiotic-cranberry juice interaction in the case of concurrent antibiotic use and the consumption of a large volume of concentrated cranberry juice.
In conclusion, the results of the studies with humans described here indicate that while the concomitant administration of CJC results in a modest delay in amoxicillin absorption and a slight delay in cefaclor absorption, their total absorption and CLR were not affected and the delays were deemed to be not clinically significant. Therefore, our results do not support a clinically relevant interaction between β-lactam antibiotics and cranberry juice at the amounts regularly consumed.