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Assistant Professor of Pharmacotherapy Department of Pharmacy Practice and Science School of Pharmacy University of Maryland 20 North Pine Street, Room 428 Baltimore, Maryland 21201-1142 fax 410/706-4725 ksummers{at}rx.umaryland.edu
Published Online, June 27, 2006. www.theannals.com, DOI 10.1345/aph.1H062
The pomegranate (Punica granatum) is an edible fruit historically complementing diets and complementary medicine practices in Mediterranean and Eastern cultures. In the US, the pomegranate fruit and its juice have recently become increasingly popular, fueled in part by the touting of its health benefits by the lay press.1 Pomegranates are rich in polyphenolic compounds and have been shown to have more antioxidant activity than either red wine or green tea.2 In vivo studies have been performed to ascertain the potential clinical benefits of pomegranates. For example, pomegranate juice extract fed to rats implanted with prostate cancer cells inhibited tumor growth and decreased secretion of prostate-specific antigen.2 In another study, humans ingesting pomegranate juice for 3 months had less inducible ischemia as measured by myocardial perfusion scans compared with control subjects (p < 0.05).3
Despite promising evidence of clinical benefit, recent pharmacokinetic studies indicate that pomegranate juice inhibits CYP3A enzyme activity. In an in vitro study examining the extent to which tropical fruits inhibit the midazolam 1'-hydroxylase activity of CYP3A, incubation with pomegranate juice led to 3.2% residual enzyme activity compared with control. In comparison, grapefruit juice resulted in 14.7% residual activity.4 In another pharmacokinetic study, Hidaka et al.5 showed that incubation of pomegranate juice (5% v/v) with human liver microsomes resulted in 1.8% residual CYP3A activity for converting carbamazepine to carbamazepine 10,11-epoxide. Further analyses revealed the inhibitory activity of pomegranate juice to be dose-dependent. Residual CYP3A activity 30 minutes after preincubation with pomegranate juice was 45.7%; in comparison, residual activity following grapefruit juice preincubation was 38.3%. In addition, both the maximum concentration and AUC of carbamazepine in rats given pomegranate juice were significantly higher than those in the control group (p < 0.05) and were comparable with values achieved in rats given grapefruit juice. Additional testing suggested that recovery of CYP3A activity occurs within 72 hours following removal of pomegranate juice ingestion. Although these 2 pharmacokinetic studies indicate that pomegranate juice has inhibitory activity comparable to that of grapefruit juice, a more recent in vitro study measuring CYP3A-catalyzed midazolam 1'-hydroxylation showed that grapefruit juice had greater inhibitory potency than pomegranate juice.6
Studies of pomegranate juice do have limitations. Since the effect of pomegranate juice on drug metabolism of rats may differ from that of humans, pharmacokinetic studies in human subjects must be performed before pharmacists make recommendations regarding concomitant use of pomegranate juice and CYP3A substrates. Also, no clinically relevant interactions involving pomegranate juice and drugs metabolized by CYP3A have yet been reported. However, at this time, pharmacists should consider the evidence that pomegranate juice may have CYP3A inhibitory activity comparable to that of grapefruit juice. When evaluating the available evidence implicating pomegranate juice as a CYP3A inhibitor, pharmacists should also note that the strong inhibitory activity of grapefruit juice initially seen in in vitro studies was eventually validated clinically through observations of rhabdomyolysis induced by concomitant administration of grapefruit juice and simvastatin.7,8 Accordingly, as the media exposure of pomegranates as a healthy "super food" continues to increase,1 pharmacists may begin encountering more patients with potential drug-food interactions.
References
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