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We are pleased that Dr. Morcos and colleagues have raised the issue of potential drug-drug interactions due to grapefruit consumption. Our work, using the JFH1/Huh7.5.1 full life-cycle model of hepatitis C virus (HCV) demonstrated that the virus is actively secreted by the cells while bound to very low density lipoprotein. This viral dependence on the cholesterol pathway suggests a new therapeutic target and an arsenal of compounds previously developed against arteriosclerosis. One of these compounds is the grapefruit flavonoid naringenin, a nontoxic antioxidant with demonstrated anticarcinogenic properties.1 Although our work demonstrated that naringenin effectively inhibits HCV secretion in vitro, these results have not been clinically validated. It is for this reason that we felt that a full discussion of the potential drug-drug interactions was beyond the scope of our original submission. However, the widespread interest in our results suggests that this discussion is warranted.

As noted by Dr. Morcos and colleagues, several furanocoumarin and flavonoids in grapefruit are known to have significant interactions with drugs including: calcium channel blockers prescribed for high blood pressure, cholesterol lowering drugs, anti-anxiety drugs such as Buspar (buspirone), birth control pills, as well as the epilepsy drug Tegretol (carbamazepine). In addition, patients on immunosuppressive medication such as Neoral (ciclosporin) or those taking protease inhibitors used to treat human immunodeficiency virus such as Norvir (ritonavir) may be in particular risk. An effect of naringenin on amphibian embryonic development has also been reported.2 A partial list of affected drugs is presented in Table 1.

Table 1. Known Drug Interactions with Grapefruit
Should Be AvoidedUse with Caution
  1. Original list compiled by Dean Elbe, BSc (Pharm), BCPP Clinical Pharmacist, Richmond, BC, Canada (www.powernetdesign.com/grapefruit).

amiodarone (Cordarone)albendazole (Albenza)indinavir (Crixivan)
astemizole (Hismanal)alfentanil (Alfenta)itraconazole (Sporanox)
atorvastatin (Lipitor)alfuzosin (Uroxatral)losartan (Cozaar)
budesonide (Entocort)almotriptan (Axert)methadone (Dolophine)
buspirone (BuSpar)aprepitant (Emend)methylprednisolone (Medrol)
cerivastatin (Baycol)aripiprazole (Abilify)midazolam (Versed)
cilostazol (Pletal)bupropion (Wellbutrin, Zyban)montelukast (Singulair)
cisapride (Propulsid, Prepulsid)carbamazepine (Tegretol)nicardipine (Cardene)
colchicinecinacalcet (Sensipar)nifedipine (Procardia)
eletriptan (Relpax)clomipramine (Anafranil)nimodipine (Nimotop)
etoposide (Vepesid)cyclosporine (Neoral)nisoldipine (Sular)
halofantrine (Halfan)darifenacin (Enablex)oxybutynin (Ditropan)
lovastatin (Mevacor)delavirdine (Rescriptor)propafenone (Rythmol)
mifepristone (Mifeprex)dextromethorphanquetiapine fumarate (Seroquel)
pimozide (Orap)diazepam (Valium)quinine
quinidine (Quinaglute, Quinidex)dofetilide (Tikosyn)ramelteon (Rozerem)
ritonavir (Norvir)efavirenz (Sustiva)saquinavir (Invirase)
sildenafil (Viagra)erlotinib (Tarceva)sertraline (Zoloft)
simvastatin (Zocor)erythromycin (Eryc, Erythromid)solifenacin (Vesicare)
sirolimus (Rapamune)eszopiclone (Lunesta)tacrolimus (Prograf)
terfenadine (Seldane)felodipine (Renedil, Plendil)tamoxifen (Nolvadex)
ziprasidone (Geodon)fexofenadine (Allegra)tamsulosin (Flomax)
 fluvoxamine (Luvox)tolterodine (Detrol)
 gefitinib (Iressa)triazolam (Halcion)
 imatinib mesylate (Gleevec/Glivec)trazodone (Desyrel)

In spite of this danger, we feel that the wide reach and rapid uptake of our work among the general public is inspiring because it demonstrates that the average patient in today's information-rich environment is actively searching for the latest research findings. In many cases, this new-found information can rapidly improve the life of patients, but in some cases overinterpretation or misunderstanding of research results could lead to undesirable effects. This potential for good or ill requires a new degree of openness from the research and medical community and a willingness to provide critical information to help patients make educated choices. In the meantime, we note that lowering cholesterol and improving your diet to include antioxidants from many fruits and vegetables has always been sound advice. It is even more important now that this link between HCV and cholesterol has been established.

References

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  • 1
    Kanno S-i, Tomizawa A, Hiura T, Osanai Y, Shouji A, Ujibe M, et al. Inhibitory effects of naringenin on tumor growth in human cancer cell lines and sarcoma S-180-implanted mice. Biol Pharm Bull 2005; 28: 527530.
  • 2
    Pérez-Coll CS, Herkovits J. Lethal and teratogenic effects of naringenin evaluated by means of an amphibian embryo toxicity test (AMPHITOX). Food Chem Toxicol 2004; 42: 299306.

Yaakov Nahmias Ph.D.* †, Martin L. Yarmush M.D., Ph.D.* †, Raymond T. Chung M.D.†, * Center for Engineering in Medicine, Shriners Burn Hospital, Boston, MA, † Massachusetts General Hospital, Harvard Medical School, Boston, MA.