**5.5. Cranberry (***Vaccinium macrocarpon***)**

American cranberry is a fruit used as a prophylactic agent against urinary tract infections [79]. Drug interactions with cranberry juice might be related to the fact that the juice is rich in flavonol glycosides, anthocyanins, proanthocyanidins, and organic and phenolic acids [80]. Izzo [81] described a total of eight cases of interaction between cranberry juice and war‐ farin, leading to changes in international normalized ratio (INR) values and bleeding. The mechanism behind this interaction might be the inhibition by cranberry flavonoids of CYP3A4 and/or CYP2C9 enzymes, which are responsible for warfarin metabolism [31,82].

It has also been shown that cranberry juice inhibits diclofenac metabolism in human liver microsomes, but this has not been demonstrated clinically in human subjects [83]. Cranberry juice may increase the bioavailability of CYP3A4 substrates (e.g., calcium antagonists or cal‐ cineurin inhibitors) as was discussed [61]. Uesawa and Mohri have demonstrated that nife‐ dipine metabolism in rat intestinal and human hepatic microsomes are inhibited by preincubation with cranberry juice. Furthermore, cranberry juice increased the nifedipine concentration in rat plasma. These findings suggest that cranberry juice might affect the plasma concentration of nifedipine in humans as well [84].

#### **5.6. Pomegranate (***Punica granatum***)**

Pomegranate is commonly eaten around the world and has been used in folk medicine for a wide variety of therapeutic purposes [85-86]. Pomegranate is a rich source of several chemi‐ cals such as pectin, tannins, flavonoids, and anthocyanins. It has been have reported that pomegranate juice influenced the pharmacokinetics of carbamazepine in rats by inhibiting enteric CYP3A activity. Such inhibition of the enteric CYP3A activity by a single exposure to pomegranate juice appears to last for approximately 3 days [56]. Nagata and others [88] found that pomegranate juice inhibited human CYP2C9 activity and increased tolbutamide bioavailability in rats. Recently, pomegranate juice was shown to potently inhibit the sulfo‐ conjugation of 1-naphthol in Caco-2 cells. It has been suggested that some constituents of pomegranate juice, most probably punicalagin, may impair the metabolic functions of the intestine (specifically sulfoconjugation) and therefore might have effects upon the bioavaila‐ bility of drugs [89].
