Citrus-Drug Interaction

Some fruit juices and fruits, especially grapefuits, can interact with numerous drugs, in many cases causing adverse effects.[1] The effect was first discovered by accident, when a test of drug interactions with alcohol used grapefruit juice to hide the taste of the ethanol.[2]

It is still best-studied with grapefruit and grapefruit juice,[1] but similar effects have more recently been seen with some (not all) other citrus fruits.[1][3][4][5][6] One medical review advises patients to avoid all citrus juices until further research clarifies the risks.[7] The interacting chemicals are found in many plants,[citation needed] and so many other foods may be affected; effects have been observed with apple juice, but their clinical significance is not yet known.[8][9][4]

Normal amounts of food and drink, such as one whole grapefruit or a small glass (200 mL (6.8 US fl oz)) of grapefruit juice, can cause drug overdose toxicity.[1] Fruit consumed three days before the medicine can still have an effect.[10] The relative risks of different types of citrus fruit have not been systematically studied.[1] Affected drugs typically have an auxiliary label saying “Do not take with grapefruit” on the container, and the interaction is elaborated on in the package insert.[11] People are also advised to ask their physician or pharmacist about drug interactions.[11]

The effects are caused by furanocoumarins (and, to a lesser extent, flavonoids). These chemicals inhibit key drug metabolizing enzymes, such as cytochrome P450 3A4 (CYP3A4). CYP3A4 is a metabolizing enzyme for almost 50% of drugs, and is found in the liver and small intestinal epithelial cells.[12] As a result, many drugs are affected. Inhibition of enzymes can have two different effects, depending on whether the drug is either

  1. metabolized by the enzyme to an inactive metaboliteor
  2. activated by the enzyme to an active metabolite.

If the active drug is metabolized by the inhibited enzyme, then the fruit will stop the drug being metabolized, leaving elevated concentrations of the medication in the body, which can cause adverse effects.[11] Conversely, if the medication is a prodrug, it needs to be metabolised to be converted to the active drug. Compromising its metabolism lowers concentrations of the active drug, reducing its therapeutic effect, and risking therapeutic failure.

Low drug concentrations can also be caused when the fruit suppresses drug absorption from the intestine.[13]



  1.  Bailey, D. G.; Dresser, G.; Arnold, J. M. O. (2012). “Grapefruit-medication interactions: Forbidden fruit or avoidable consequences?”Canadian Medical Association Journal185 (4): 309–316. doi:10.1503/cmaj.120951PMC 3589309Freely accessiblePMID 23184849.
  2. Jump up ^ Bailey, David G.; Malcolm, J.; Arnold, O.; David Spence, J. (2002-01-04). “Grapefruit juice-drug interactions”British Journal of Clinical Pharmacology46 (2): 101–110. doi:10.1046/j.1365-2125.1998.00764.x.
  3. Jump up to: a b
  4. Jump up to: a b c d e Bailey, D (June 2003). “Bergamottin, lime juice, and red wine as inhibitors of cytochrome P450 3a4 activity: comparison with grapefruit juice,”. Clinical Pharmacology & Therapeutics73 (6): 529–537. doi:10.1016/S0009-9236(03)00051-1.
  5. Jump up to: a b c d Widmer, Wilbur (31 May 2006). “One Tangerine/Grapefruit Hybrid (Tangelo) Contains Trace Amounts of Furanocoumarins at a Level Too Low To Be Associated with Grapefruit/Drug Interactions”Journal of Food Science70 (6): c419–c422. doi:10.1111/j.1365-2621.2005.tb11440.x.
  6. Jump up to: a b c d e f g “Hybrid grapefruit safe for prescription meds”. Retrieved 2013-01-28.
  7. Jump up to: a b c d e Saito, Mitsuo; Hirata-Koizumi, Mutsuko; Matsumoto, Mariko; Urano, Tsutomu; Hasegawa, Ryuichi (2005). “Undesirable effects of citrus juice on the pharmacokinetics of drugs: focus on recent studies”. Drug Safety28 (8): 677–694. doi:10.2165/00002018-200528080-00003PMID 16048354.
  8. Jump up to: a b c d e “Fruit juice ‘could affect drugs'”BBC News. 20 August 2008.
  9. Jump up ^
  10. Jump up to: a b c Greenblatt DJ, von Moltke LL, Harmatz JS, et al. (August 2003). “Time course of recovery of cytochrome p450 3A function after single doses of grapefruit juice”. Clinical Pharmacology and Therapeutics74 (2): 121–9. doi:10.1016/S0009-9236(03)00118-8PMID 12891222.
  11. Jump up to: a b c Mitchell, Steve (19 February 2016). “Why Grapefruit and Medication Can Be a Dangerous Mix”Consumer Reports. Retrieved 4 May 2016.
  12. Jump up to: a b c d e f g Pirmohamed, Munir (12 January 2013). “Drug-grapefruit juice interactions: Two mechanisms are clear but individual responses vary”. BMJ346 (7890): 9. doi:10.1136/bmj.f1.
  13. Jump up ^ FDA Consumer update

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