Grapefruit-medication interactions

This mini-review discusses key scientific concepts and clinical implications of grapefruit-drug interactions. Grapefruit and certain related citrus fruits (Seville orange, pomelo, lime) are foods considered to be healthful but having the potential for a pharmacokinetic interaction causing enhanced oral bioavailability of certain drugs. The active constituents are most likely furanocoumarins. Varieties of sweet oranges neither contain furanocoumarins nor produce this interaction. The interaction involves irreversible inactivation of the enzyme CYP 3A4 involved in the metabolism of many drugs. The key issues are adverse effects occurring in routine clinical practice; some of them are discussed here. While grapefruit-drug interactions are generally considered to be negative occurrences to be avoided, there has been consideration to use this interaction to achieve beneficial therapeutic goals i.e. lowering of drug dosages. Unfortunately, the effect has been highly variable among individuals and studies. Development of a standard drug on the basis of furanocoumarins may be a solution. In conclusion, grapefruit and certain other citrus fruits have the potential for an interaction causing enhanced bioavailability of some oral drugs. This action carries the risk of adverse events from excessive effect, particularly for drugs with overdose toxicities. This necessitates an understanding of this interaction and the application of such in the safe and effective use of drugs in general practice.

Key words: grapefruit, pharmacotherapy, pharmacokinetics, drug interaction,
nutrition.

Published: 16.02.2017

References:

• Adukwu E.C., Allen S.C., Phillips C.A. (2012) The anti-biofilm activity of lemongrass (Cymbopogon flexuosus) and grapefruit (Citrus paradisi) essential oils against five strains of Staphylococcus aureus. J. Appl. Microbiol., 113(5): 1217–1227.
• Agosti S., Casalino L., Bertero G. et al. (2012) A dangerous fruit juice. Am. J. Emerg. Med., 30(1): 248.e5–248.e8.
• Alam M.A., Subhan N., Rahman M.M. et al. (2014) Effect of citrus flavonoids, naringin and naringenin, on metabolic syndrome and their mechanisms of action. Adv. Nutr., 5(4): 404–417.
• Bailey D.G., Dresser G., Arnold J.M. (2013) Grapefruit-medication interactions: forbidden fruit or avoidable consequences? CMAJ, 185(4): 309–316.
• Chudnovskiy R., Thompson A., Tharp K. et al. (2014) Consumption of clarified grapefruit juice ameliorates high-fat diet induced insulin resistance and weight gain in mice. PLoS One, 9(10): e108408.
• Cvetnić Z., Vladimir-Knezević S. (2004) Antimicrobial activity of grapefruit seed and pulp ethanolic extract. Acta Pharm., 54(3): 243–250.
• Dasgupta A., Reyes M.A., Risin S.A., Actor J.K. (2008) Interaction of white and pink grapefruit juice with acetaminophen (paracetamol) in vivo in mice. J. Med. Food, 11(4): 795–798.
• Dreier J.P., Endres M. (2004) Statin-associated rhabdomyolysis triggered by grapefruit consumption. Neurology, 62(4): 670.
• Dresser G.K., Bailey D.G., Carruthers S.G. (2000) Grapefruit juice — felodipine interaction in the elderly. Clin. Pharmacol. Ther., 68(1): 28–34.
• Ducharme M.P., Warbasse L.H., Edwards D.J. (1995) Disposition of intravenous and oral cyclosporine after administration with grapefruit juice. Clin. Pharmacol. Ther., 57(5): 485–491.
• El-Lakkany N.M., Seif el-Din S.H., Badawy A.A., Ebeid F.A. (2004) Effect of artemether alone and in combination with grapefruit juice on hepatic drug-metabolising enzymes and biochemical aspects in experimental Schistosoma mansoni. Int. J. Parasitol., 34(12): 1405–1412.
• Goldbart A., Press J., Sofer S., Kapelushnik J. (2000) Near fatal acute colchicine intoxication in a child. A case report. Eur. J. Pediatr., 159(12): 895–897.
• Grande L.A., Mendez R.D., Krug R.T., Verschuyl E.J. (2009) Attention — grapefruit! Lancet, 373(9670): 1222.
• Guo L.Q., Chen Q.Y., Wang X. et al. (2007) Different roles of pummelo furanocoumarin and cytochrome P450 3A5*3 polymorphism in the fate and action of felodipine. Curr. Drug Metab., 8(6): 623–630.
• Heggers J.P., Cottingham J., Gusman J. et al. (2002) The effectiveness of processed grapefruit-seed extract as an antibacterial agent: II. Mechanism of action and in vitro toxicity. J. Altern. Complement. Med., 8(3): 333–340.
• Hermans K., Stockman D., van den Branden F. (2003) Grapefruit and tonic: a deadly combination in a patient with the long QT syndrome. Am. J. Med., 114(6): 511–512.
• Hollander A.A., van Rooij J., Lentjes G.W. et al. (1995) The effect of grapefruit juice on cyclosporine and prednisone metabolism in transplant patients. Clin. Pharmacol. Ther., 57(3): 318–324.
• Jourdan P.S., McIntosh C.A., Mansell R.L. (1985) Naringin Levels in Citrus Tissues: II. Quantitative Distribution of Naringin in Citrus paradisi MacFad. Plant Physiol., 77(4): 903–908.
• Jung U.J., Lee M.K., Jeong K.S., Choi M.S. (2004) The hypoglycemic effects of hesperidin and naringin are partly mediated by hepatic glucose-regulating enzymes in C57BL/KsJ-db/db mice. J. Nutr., 134(10): 2499–2503.
• Kanazawa S., Ohkubo T., Sugawara K. (2001) The effects of grapefruit juice on the pharmacokinetics of erythromycin. Eur. J. Clin. Pharmacol., 56(11): 799–803.
• Karch A.M. (2004) The grapefruit challenge: the juice inhibits a crucial enzyme, with possibly fatal consequences. Am. J. Nurs., 104(12): 33–35.
• Lundahl J., Regårdh C.G., Edgar B., Johnsson G. (1995) Relationship between time of intake of grapefruit juice and its effect on pharmacokinetics and pharmacodynamics of felodipine in healthy subjects. Eur. J. Clin. Pharmacol., 49(1–2): 61–67.
• Mahgoub A.A. (2002) Grapefruit juice potentiates the anti-inflammatory effects of diclofenac on the carrageenan-induced rat’s paw oedema. Pharmacol. Res., 45(1): 1–4.
• Mahmoud A.M., Ashour M.B., Abdel-Moneim A., Ahmed O.M. (2012) Hesperidin and naringin attenuate hyperglycemia-mediated oxidative stress and proinflammatory cytokine production in high fat fed/streptozotocin-induced type 2 diabetic rats. J. Diabetes Complications, 26(6): 483–490.
• Malhotra S., Bailey D.G., Paine M.F., Watkins P.B. (2001) Seville orange juice-felodipine interaction: comparison with dilute grapefruit juice and involvement of furocoumarins. Clin. Pharmacol. Ther., 69(1): 14–23.
• Mazokopakis E.E. (2008) Unusual causes of rhabdomyolysis. Intern. Med. J., 38(5): 364–367.
• Murunga A.N., Miruka D.O., Driver C. et al. (2016) Grapefruit derived flavonoid naringin improves ketoacidosis and lipid peroxidation in type 1 diabetes rat model. PLoS One, 11(4): e0153241.
• Nieminen T.H., Hagelberg N.M., Saari T.I. et al. (2010) Grapefruit juice enhances the exposure to oral oxycodone. Basic Clin. Pharmacol. Toxicol., 107(4): 782–788.
• Okura T., Ozawa T., Ito Y. et al. (2008) Enhancement by grapefruit juice of morphine antinociception. Biol. Pharm. Bull., 31(12): 2338–2341.
• Pillai U., Muzaffar J., Sen S., Yancey A. (2009) Grapefruit juice and verapamil: a toxic cocktail. South Med. J., 102(3): 308–309.
• Punithavathi V.R., Anuthama R., Prince P.S. (2008) Combined treatment with naringin and vitamin C ameliorates streptozotocin-induced diabetes in male Wistar rats. J. Appl. Toxicol., 28(6): 806–813.
• Qinna N.A., Ismail O.A., Alhussainy T.M. et al. (2016) Evidence of reduced oral bioavailability of paracetamol in rats following multiple ingestion of grapefruit juice. Eur. J. Drug Metab. Pharmacokinet., 41(2): 187–195.
• Seidegård J., Randvall G., Nyberg L., Borgå O. (2009) Grapefruit juice interaction with oral budesonide: equal effect on immediate-release and delayed-release formulations. Pharmazie, 64(7): 461–465.
• Sridharan K., Sivaramakrishnan G. (2016) Interaction of citrus juices with cyclosporine: systematic review and meta-analysis. Eur. J. Drug Metab. Pharmacokinet., 41(6): 665–673.
• Sirovina D., Oršolić N., Gregorović G., Končić M.Z. (2016) Naringenin ameliorates pathological changes in liver and kidney of diabetic mice: a preliminary study. Arh. Hig. Rada Toksikol., 67(1): 19–24.
• Takanaga H., Ohnishi A., Murakami H. et al. (2000) Relationship between time after intake of grapefruit juice and the effect on pharmacokinetics and pharmacodynamics of nisoldipine in healthy subjects. Clin. Pharmacol. Ther., 67(3): 201–214.
• Varis T., Kivistö K.T., Neuvonen P.J. (2000) Grapefruit juice can increase the plasma concentrations of oral methylprednisolone. Eur. J. Clin. Pharmacol., 56(6–7): 489–493.
• von Woedtke T., Schlüter B., Pflegel P. et al. (1999) Aspects of the antimicrobial efficacy of grapefruit seed extract and its relation to preservative substances contained. Pharmazie, 54(6): 452–456.
• Xulu S., Oroma Owira P.M. (2012) Naringin ameliorates atherogenic dyslipidemia but not hyperglycemia in rats with type 1 diabetes. J. Cardiovasc. Pharmacol., 59(2): 133–141.