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Health and Drug Alerts

Grapefruit juice: potential drug interactions

James Maskalyk
CMAJ August 06, 2002 167 (3) 279-280;
James Maskalyk
Editorial Fellow,
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Reason for posting: Grapefruit juice interacts with a number of medications. This unusual discovery was made serendipitously in 1989 during an experiment designed to test the effect of ethanol on a calcium-channel blocker.1 The observed response was later determined to be due to the grapefruit juice delivery vehicle rather than the alcohol. In the past decade, the list of drug interactions with grapefruit juice has expanded to include several classes of medication, precipitating a recent advisory from Health Canada.2

The interaction: As little as 250 mL of grapefruit juice can change the metabolism of some drugs.3 This drug–food interaction occurs because of a common pathway involving a specific isoform of cytochrome P450 — CYP3A4 — present in both the liver and the intestinal wall. Studies suggest that grapefruit juice exerts its effect primarily at the level of the intestine.4

After ingestion, a substrate contained in the grapefruit binds to the intestinal isoenzyme, impairing first-pass metabolism directly and causing a sustained decrease in CYP3A4 protein expression.5 Within 4 hours of ingestion, a reduction in the effective CYP3A4 concentration occurs, with effects lasting up to 24 hours.6 The net result is inhibition of drug metabolism in the intestine and increased oral bioavailability. Because of the prolonged response, separating the intake of the drug and the juice does not prevent interference.

Individuals express CYP3A4 in different proportions, those with the highest intestinal concentration being most susceptible to grapefruit juice–drug interactions.5 An effect is seen with the whole fruit as well as its juice, so caution should be exercised with both.7 The precise chemical compound in grapefruit that causes the interaction has not been identified. There is no similar reaction with orange juice, although there is some suspicion that “sour oranges” such as the Seville variety, may have some effect.8 A recent study, however, that tested the known interference of grapefruit juice with cyclosporine showed no similar effect with Seville oranges.9

There is some interest in the potential therapeutic benefit of adding grapefruit juice to a drug regimen to increase oral bioavailability.3 The limitation is the individual variation in patient response. However, if the chemical that causes grapefruit's CYP3A4 inhibition is elucidated, there may be an opportunity to modulate that pathway in a controlled fashion.

What to do: Much of the data obtained on grapefruit juice–drug interactions involved measuring serum drug concentrations in small numbers of healthy volunteers. Because of the limited data and only occasional case reports,10 it is difficult to quantify the clinical significance for individual patients. One may assume that the interaction occurs primarily with oral medicines, and only with those that share the CYP3A4 metabolism pathway, with the consequence being increased oral bioavailability, higher serum drug concentrations and associated adverse effects.

Physicians should review medication lists often, with the goal of warning patients about adverse interactions. A list of medicines with which patients should not consume grapefruit is provided in Table 1.3,11,12 In the case of several medications that share the CYP3A4 metabolism pathway, but for which a clinical effect has not been elucidated or is theoretical, patients should be advised to consume grapefruit cautiously and be monitored for toxicity.

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Table 1.

James Maskalyk Editorial Fellow, CMAJ

References

  1. 1.↵
    Bailey DG, Spence JD, Edgar B, Bayliff CD, Arnold JM. Ethanol enhances the hemodynamic effects of felodipine. Clin Invest Med 1989;12:357-62.
    OpenUrlPubMed
  2. 2.↵
    Health Canada is advising Canadians not to take certain drugs with grapefruit juice. Ottawa: Health Canada; 2002 Jun 21. Available: www.hc-sc.gc.ca/english/protection/warnings/2002/2002_49e.htm (accessed 2002 Jul 9).
  3. 3.↵
    Kane G, Lipsky J. Drug–grapefruit juice interactions. Mayo Clin Proc 2000;75:933-42.
    OpenUrlCrossRefPubMed
  4. 4.↵
    Lundahl J, Regardh CJ, Edgar B, Johnsson G. Effects of grapefruit juice ingestion — pharmacokinetics and haemodynamics of intravenously and orally administered felodipine in healthy men. Eur J Pharmacol 1997;52:139-45.
    OpenUrlCrossRef
  5. 5.↵
    Lown KS, Bailey DG, Fontana RJ, Janardan SK, Adair CH, Fortlage LA, et al. Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression. J Clin Invest 1997;99(10):2545-53.
    OpenUrlCrossRefPubMed
  6. 6.↵
    Lundahl J, Regardh CG, Edgar B, Johnsson G. Relationship between time of intake of grapefruit juice and its effect on pharmacokinetics and pharmacodynamics of felodipine in healthy subjects. Eur J Clin Pharmacol 1995;49:61-7.
    OpenUrlPubMed
  7. 7.↵
    Bailey DG, Kreeft JH, Munoz C, Freeman DJ, Bend JR. Grapefruit juice–felodipine interaction: effect of segments and an extract from unprocessed fruits [abstract]. Clin Pharmacol Ther 2000;67:107.
    OpenUrl
  8. 8.↵
    Malhotra S, Bailey DG, Paine MF, Watkins PB Seville orange juice–felodipine interaction: comparison with dilute grapefruit juice and involvement of furocoumarins. Clin Pharmacol Ther 2001;69(1):14-23.
    OpenUrlCrossRefPubMed
  9. 9.↵
    Edwards DJ, Fitzsimmons ME, Schuetz EG, Yasuda K, Ducharme MP, Warbasse LH, et al. 6´,7´-Dihydrobergamottin in grapefruit juice and Seville orange juice: effects on cyclosporine disposition, enterocyte CYP3A4, and P-glycoprotein. Clin Pharmacol Ther 1999;65:237-44.
    OpenUrlCrossRefPubMed
  10. 10.↵
    Goldbart A, Press J, Sofer S, Kapelushnik J. Near fatal acute colchicine intoxication in a child. A case report. Eur J Pediatr 2000;159(12):895-7.
    OpenUrlCrossRefPubMed
  11. 11.↵
    Drug administration and grapefruit juice. In: Compendium of pharmaceuticals and specialties. Ottawa: Canadian Pharmicists Association; 2001. p. L63-65.
  12. 12.↵
    McNeece J. Interactions between grapefruit juice and some drugs available in Australia [table]. Australian Prescriber 2002;25(2). Available: www.australianprescriber.com (accessed 2002 July 9).
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Grapefruit juice: potential drug interactions
James Maskalyk
CMAJ Aug 2002, 167 (3) 279-280;

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