The Inhibitory Effect of Cranberry Juice on Phenytoin Metabolism by Human Liver Microsomes

Abstract

CYP2C9 is involved in the metabolism of many drugs such as warfarin and phenytoin（PHT). It is well known that some foods cause pharmacokinetic alterations of drugs and lead to toxicity. Regarding the interaction caused by cranberry juice（CrJ), its influence on the metabolism of warfarin, a CYP2C9 substrate, is controversial. In addition, information concerning the influence of CrJ on the pharmacokinetics of other substrate drugs of CYP2C9 is not available. To examine the inhibitory effect of CrJ on the metabolism of PHT, we performed experiments using a baculovirus expression microsome system and human liver microsome assay. CrJ concentration-dependently inhibited the substrate metabolism both in a baculovirus-expressed microsome system and in human liver microsome assay. These data support the idea that CrJ inhibits CYP2C9 activity, and the subsequent metabolism of drugs metabolized by CYP2C9. In this study, we did not identify the specific substance(s）which inhibits CYP2C9 activity. However, as CrJ did not enhance the PHT accumulation in 3D-HepG2 cells, it is thought that the penetration into hepatic cells of inhibitory substances in CrJ seems to be small.

Cranberry juice suppressed the diclofenac metabolism by human liver microsomes, but not in healthy human subjects

“…In this study, CrJ also concentration‐dependently inhibited diclofenac metabolism, and the IC 50 value was estimated to be 1.44%. Previously, we found that phenytoin metabolism was suppressed by CrJ in human liver microsome assay [9]. These observations support the hypothesis that CrJ inhibits the metabolism of CYP2C9 substrates.…”

“…In a previous in vitro study, CrJ inhibited the hydroxylation of flurbiprofen, a CYP2C9 substrate, to approximately 50% by human liver microsomes [8]. We also found that CrJ significantly inhibited the metabolism of phenytoin, another CYP2C9 substrate, in vitro [9]. Therefore, it is anticipated that CrJ inhibits CYP2C9‐mediated drug metabolism in vivo .…”

“…These findings lead us to speculate that the concentration of unbound‐form diclofenac exposed to CYP enzymes was higher in vitro than in vivo , and consequently the inhibitory effect of CrJ on the metabolism of diclofenac seems greater in the in vitro study. We have already reported that CrJ inhibited phenytoin metabolism by human liver microsomes, but not in cultured hepatic cells [9]. These data indicate that the penetration of CrJ‐containing inhibitory substance(s) into cells was small, which may be another mechanism for the difference of CrJ effect in vitro from in vivo .…”

Chemistry, Pharmacology and Health Benefits of Anthocyanins

“…These observations were also confirmed by an in vivo study (Uesawa and Mohri, ). Cranberry juice was found to diminish CYP2C9 activity versus diclofenac and phenytoin in human liver microsomes, although this occurrence was not observed clinically (Ushijima et al ., ; Ushijima et al ., ). In addition to the isoforms 3A4 and 2C9, anthocyanins and their aglycones were found to possess weak inhibitory activity on CYP2D6 although 1000‐fold lower with respect to grapefruit‐derived furanocoumarins; on the basis of this observation, interference with drug metabolism by CYP2D6 is highly unlikely (Dreiseitel et al ., ).…”

Merging the old with the new: a cybermedicine marriage for oncology interactions with traditional herbal therapies and complementary medicines

“…Cranberry can inhibit CYP2C9 and 3A4, therefore it can theoretically interact with ACDs that are substrates of these isozymes (Table 1). In vitro studies have shown cranberry juice to inhibit CYP2C9-mediated metabolism of phenytoin (Ushijima et al, 2009a). Furthermore, the international normalized ratios of warfarin, another CYP2C9 substrate, were shown to be elevated in numerous case reports (Grant, 2004;Griffiths et al, 2008;Hamann et al, 2011;Paeng et al, 2007;Suvarna et al, 2003;Welch and Forster, 2007).…”