Questions about the interaction of drugs with grapefruit juice have increased. I have therefore collated available data to produce a table which may help when assessing the significance and clinical relevance of an interaction. The full table is available with this article on the Australian Prescriber web site.
The CYP3A4 enzyme system is found in the liver and in enterocytes. Some drugs are therefore metabolised as they are absorbed by the enterocytes. Drugs can also be pumped back into the intestinal lumen by a P-glycoprotein (Pgp) transporter. Pgp and CYP3A4 may therefore act in tandem as a barrier to drugs getting from the gut to the systemic circulation. Inhibition of either or both systems can increase the bioavailability of a drug.1 Grapefruit juice appears to selectively inhibit CYP3A4 in the small intestine. However, the interactions are not simple competition for substrate metabolism, grapefruit juice acts by selective post-translational down regulation of enzyme expression in the intestinal wall.2,3 The inhibition can last up to 24 hours with a maximal effect when the juice is given with the drug or up to four hours before the drug.4
All interactions studied so far have used grapefruit juice.5 There are no useful studies with whole grapefruit.6 Sweet orange juice does not interact, however, Seville (or bitter) orange juice can inhibit CYP3A4 (although this does not affect cyclosporin7).
Of the many interactions studied only cyclosporin can be definitely said to have a clinically significant interaction. The clinical significance of increased concentrations of sirolimus and tacrolimus is less clear. Other interactions which may be clinically significant occur with amiodarone, atorvastatin, carbamazepine, felodipine and simvastatin.
Martin J, Fay M. Cytochrome P450 interactions: are they clinically relevant? Aust Prescr 2001;24:10-2.
- Garvan C, Kane GC, Lipsky JJ. Drug-grapefruit juice interactions. Mayo Clin Proc 2000;75:933-42.
- 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;99:2545-53.
- Bailey DG, Malcolm J, Arnold O, Spence JD. Grapefruit juice-drug interactions [review]. Br J Clin Pharmacol 1998;46:101-10.
- 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.
- Abernethy DR. Grapefruits and drugs: when is statistically significant clinically significant? [letter]. J Clin Invest 1997;99:2297-8.
- Drug interactions with grapefruit juice. WHO Drug Information 1997;11:70-1.
- 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.