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Drug Interactions with Grapefruit and Related Citrus Fruits Excerpted from Food-Medication Interactions 14th Edition
Many drugs interact with grapefruit (juice, segments, extract and certain related citrus fruits, e.g. Seville
oranges, pummelos, and some exotic orange varieties). Several components in grapefruit called
furanocoumarins (two of the most common are bergamottin and 6’7’-dihydroxybergamottin) irreversibly inhibit
cytochrome P450 3A4 isoenzymes (3A4) in the intestinal wall, decreasing the pre-systemic metabolism of
affected drugs taken up to 72 hours after grapefruit consumption. Intestinal 3A4 activity can remain inhibited
during this time, as the body produces more enzymes. Greater amounts of 3A4-metabolized drugs can then
enter the systemic circulation. The resulting increase in drug levels can lead to an increase in therapeutic
effect, adverse effects and/or toxicity. Interactions are most pronounced for drugs that normally undergo a
large amount of pre-systemic metabolism (low oral bioavailability). Limited evidence indicates that following
intake of very large amounts of grapefruit, hepatic 3A4 may also be inhibited.
If a drug’s metabolic pathways are known, it may be possible to predict if an interaction with grapefruit could
occur. Grapefruit weakly inhibits intestinal cell wall p-glycoprotein (p-GP), an efflux pump in enterocytes that
actively secretes some absorbed drugs back into the gut lumen. Not all 3A4-metabolized drugs are p-GP
substrates. Organic anion transporting polypeptide (OATP) is another transporter system affected by
grapefruit. Drugs handled by OATP may have decreased
absorption when taken with grapefruit, possibly
leading to loss of efficacy. Emerging information indicates bergamottin inactivates cytochrome p450 2B6 and
3A5 isoenzymes, potentially causing drug interactions with substrates of these isoenzymes.
1 -Manufacturer recommends avoidance.
7 - Not metabolized by 3A4, no interaction suspected.
2 - Use with grapefruit/related citrus only on advice of a
8 - No interaction when drug administered parenterally.
3 - Serum/Plasma level monitoring required/recommended.
10 - Blood levels/bioavailability decreased.
4 - Minor interaction, not clinically significant.
11 – Risk higher in CYP 2D6 poor metabolizers.
5 - Interaction suspected, but no formal studies.
6 - No formal studies, but lacks a cardiotoxic metabolite. Medications that should be avoided with grapefruit
terfenadine (Seldane)9 ziprasidone (Geodon)5
Use with grapefruit with caution
imatinib mesylate (Gleevec/Glivec)5 sertraline (Zoloft)
Medications with no significant interaction with grapefruit
Drugs in this section have all been studied with grapefruit, and found to have either a minimal/negligible
Medications considered safe for use with grapefruit
Table compiled by Dean Elbe BSc (Pharm), BCPP
Clinical Pharmacist, Richmond, BC, Canada
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