Grapefruit Can Dramatically Increase Medication Potency

Daniel Weiss, Senior Editor
Published Online: Tuesday, December 11, 2012
Follow Pharmacy_Times:
Compounds in grapefruit can interact with a growing number of oral medications to produce serious side effects, according to a review of previous studies.

Grapefruit can interact with a broad range of oral medications to significantly increase their effects, according to a review of previous studies published online on November 26, 2012, by the Canadian Medical Association Journal. At least 85 oral medications can have such interactions with grapefruit, 43 of which can lead to serious side effects, and many of these have been introduced just in the last few years.
Compounds in grapefruit called furanocoumarin chemicals are the cause of the increased medication potency. These chemicals interact with the cytochrome P450 3A4 (CYP3A4) enzyme, found in the small intestine and liver, which partially inactivates many medications under normal circumstances. However, the grapefruit chemicals impair the action of CYP3A4, allowing the bioactivity of some medications to reach much higher levels than normal, potentially producing adverse effects. Furanocoumarin chemicals are also found in Seville oranges (used to make marmalade), limes, and pomelos, but not in sweet oranges such as navels and Valencias.
Even a relatively small amount of grapefruit can have a large effect on drug concentration levels. For example, a single serving of grapefruit juice (200-250 ml) or a whole grapefruit combined with the antihypertensive felodipine has been shown to yield a systemic drug concentration 3 times that seen with equivalent water intake. Repeated intake led to even larger effects; drinking 250 ml of grapefruit juice 3 times per day for 6 days led to a systemic drug concentration 5 times that seen with water. However, the effect can vary greatly from patient to patient. Different individuals who took felodipine with a 250-ml serving of grapefruit juice had systemic concentrations ranging from 0 to 8 times that observed with water.
Medications are at risk of being made more potent in interaction with grapefruit if they are taken orally, have very low to intermediate intrinsic oral bioavailability, and are metabolized by CYP3A4. Patients aged 45 years and older are at increased risk of grapefruit-drug interactions due to their increased consumption of grapefruit and prescription medications. Elderly patients are most vulnerable because they are less able to compensate for high systemic drug concentrations and because pronounced pharmacokinetic interaction has been found in those 70 years of age and older.
Serious adverse events that have been reported due to grapefruit-drug interactions include heart rhythm problems, heart blockage, muscle deterioration, kidney failure, and blood clots. Some of the most commonly prescribed drugs in 2011—the statins atorvastatin and simvastatin—are identified by the review as having a high (atorvastatin) or very high (simvastatin) risk of interaction with grapefruit. When combined with regular consumption of grapefruit juice (250-400 ml, 3 times per day for 2-4 days), the systemic concentration of atorvastatin was 180% to 250% of that seen with water. When combined with a high volume of grapefruit juice (400 ml, 3 times per day for 3 days), simvastatin had a systemic concentration of 700% of that seen with water.
Other medications judged by the review authors to be at very high risk of interaction with grapefruit were: the anti-infectives halofantrine and maraviroc; the cardiovascular agent dronedarone; and the CNS agents ketamine (oral) and lurasidone.

Here is a list of oral medications with the potential to become more potent in interaction with grapefruit that have been approved by the FDA in the last 5 years:
Oncology drugs:
Crizotinib (Xalkori) (High risk)
Everolimus (Afinitor) (High risk)
Lapatinib (Tykerb) (High risk)
Nilotinib (Tasigna) (High risk)
Pazopanib (Votrient) (High risk)
Vandetanib (Vandetanib) (High risk)
Vemurafenib (Zelboraf) (High risk)
Anti-infective agents:
Maraviroc (Selzentry) (Very high risk)
Rilpivirine (Edurant) (High risk)
Cardiovascular agents:
Dronedarone (Multaq) (Very high risk)
Rivaroxaban (Xarelto) (Intermediate risk)
Ticagrelor (Brilinta) (High risk)
CNS agents:
Lurasidone (Latuda) (Very high risk)
Everolimus (Zortress) (High risk)
Urinary tract agents:
Fesoterodine (Toviaz) (Intermediate risk)
Silodosin (Rapaflo) (Intermediate risk)

Update: To see a  complete list of drugs that interact with grapefruit along with associated adverse events, level of risk, and potential alternative medications, click here.

Related Articles
The FDA is warning health care professionals and patients about prescribing and dispensing errors related to confusion between the antidepressant Brintellix and the blood thinner Brilinta.
The results of the PEGASUS-TIMI 54 trial could potentially lead to a change in clinical guidelines to extend the currently recommended 12 months of ticagrelor therapy.
Similar to the DAPT trial on dual antiplatelet therapy beyond a year, the PEGASUS-TIMI 54 trial examined longer-term duration of ticagrelor therapy.
The results of the ANNEXA-R trial that sought to determine whether andexanet alfa could reverse the effects of rivaroxaban are promising
Latest Issues