A grapefruit a day for patients infected with hepatitis C? (2008)

We read with great interest the article by Nahmias et al.1 documenting the potential of naringenin, a grapefruit flavonoid, to reduce hepatitis C virus (HCV) secretion in the Huh-7.5.1 human hepatoma/JFH1 cell model. These findings further document the important advances that are possible with this vastly improved in vitro model of HCV infection. Although the results offer new insight into a promising and novel HCV therapeutic target in the long term, we are struck by the potential short-term impact of this information in the hands of the general public. Since the online release of this manuscript in January 2008, a Google search of the terms “grapefruit” and “hepatitis” in February 2008 provides links to hundreds of Web sites, many of which represent HCV patient forums, nutritional supplement sellers, and internet “blogs”. The wide reach and rapid uptake of high-impact scientific journals, such as HEPATOLOGY, among the lay community is truly fascinating. Because of this relatively new and growing phenomenon, we ponder the role of the journal in considering the potential impact of published results within the lay community and how an important scientific finding might be overinterpreted or misused. As mentioned by the authors, several furanocoumarins and flavonoids in grapefruit have been shown to inhibit drug-metabolizing enzymes, including cytochrome P450 (CYP) 3A4 as well as drug transporters such as P-glycoprotein and organic anion transporting polypeptide.2-5 CYP3A4 is responsible for the metabolism of more than 50% of approved drugs, and consumption of grapefruit-containing products has the potential to cause dangerous food–drug interactions with many medications HCV patients may be taking.6 Grapefruit is classified by the U.S. Food and Drug Administration as a moderate inhibitor of CYP3A4, which is defined as any agent that increases the systemic exposure of drugs metabolized through this pathway by two-fold to five-fold.7 Increases of up to 15-fold have been reported.8 Interestingly, there are numerous specifically targeted antiviral therapies for HCV (STAT-C) in various stages of clinical development, with the potential to improve therapeutic outcomes in patients beyond what is currently possible with the combination of peginterferon and ribavirin. At least a number of these orally administered compounds are known to be substrates of CYP3A4 and other drug transporters, and thus systemic exposures may increase significantly if coadministered with grapefruit-containing products. Patients who are coinfected with HCV and human immunodeficiency virus may be at particular risk, because many components of antiretroviral therapy similarly interact with CYP3A4 and drug transporters, resulting in grapefruit being contraindicated with many of these medications. The findings by Nahmias et al. may provide valuable insight toward identification of new targets against HCV. Perhaps in the future, combining one or more of the STAT-C compounds with a compound that inhibits HCV secretion may lead to large improvement in clinical outcomes. Until then, patients infected with HCV who read articles with titles such as “Grapefruit Compound May be the Key to Battling Hepatitis C” may be tempted to supplement their diet with grapefruit, risking potential adverse drug reactions unnecessarily. The patient community needs to understand that the study results were generated using an in vitro model of HCV with the aim of providing scientific information which may be used in the future to develop novel treatments for chronic hepatitis C and be made aware that this study is not suggesting chronic hepatitis C patients begin consuming a grapefruit-rich diet. Peter N. Morcos*, Barbara Brennan*, Patrick F. Smith*, * Department of Clinical Pharmacology, Virology Clinical Research and Experimental Medicine, Hoffmann-La Roche Inc., Nutley, NJ and Palo Alto, CA.