Grapefruit is a citrus fruit that is low in calories; rich in vitamin C, potassium, and dietary fiber; and has been a recommended fruit of the American Heart Association’s “Healthy Heart Campaign.”1 The authors of a study2 that used grapefruit juice to mask the taste of ethanol inadvertently discovered an interaction between grapefruit and the calcium channel blocker felodipine (Plendil). They observed that patients who consumed grapefruit juice had felodipine plasma concentrations two to three times higher than normal levels.2
|Clinical recommendation||Evidence rating||References||Comments|
|Patients should discontinue grapefruit consumption for 72 hours before use of a drug that may interact with it.||C||5, 6||The potential for a grapefruit-drug interaction persists for up to 72 hours according to one study.5|
|Potential grapefruit-drug interactions cannot be avoided by separating times of medication administration and grapefruit consumption.||C||5, 6||Studies have shown that consuming 8 oz of grapefruit juice may decrease the concentration of intestinal cytochrome P450 3A4 by 47 percent for 24 to 72 hours.|
The discovery of this and other clinically significant interactions may have caused health care professionals to hesitate before universally recommending grapefruit as part of a healthy diet. Because grapefruit-drug interactions exist, strategies should be devised to manage potential interactions. A patient may choose to exclude grapefruit from his or her diet and substitute other fruits, including any other citrus.3 However, if the patient wishes to continue to consume grapefruit products, an alternate medication that does not have the potential to interact with grapefruit may be prescribed.
MECHANISM OF INTERACTION
The characteristics of medications that interact with grapefruit are well defined. The most significant of these characteristics is metabolism by the intestinal cytochrome P450 3A4 (CYP 3A4) system. CYP 3A4 is found in the liver and intestinal tract. Intestinal CYP 3A4 concentration can be decreased by 47 percent within four hours of grapefruit consumption.4 One study5 has shown that the interaction persists for up to 72 hours; therefore, it would be prudent to avoid grapefruit products for 72 hours before taking a medication with which they may interact.
Another study6 reported that consuming 8 oz of grapefruit juice can inhibit intestinal CYP 3A4 concentration for 24 to 72 hours. Therefore, separating the times of medication administration and grapefruit consumption is not a plausible solution.5,6 It is important to note that because of genetic polymorphism, persons have varying amounts of intestinal CYP 3A4; consequently, the extent of an interaction is not predictable from patient to patient.7,8
The substance or substances in grapefruit that inhibit intestinal CYP 3A4 have not been identified. In addition, grapefruit may decrease the intestinal transport of drugs into the circulation.7 Because intestinal CYP 3A4 is affected, the interaction will only occur with oral formulations. Studies of the intravenous form of drugs that are substrates of hepatic CYP 3A4 and have the potential to interact with grapefruit failed to demonstrate any effect on plasma concentration.4
Medications metabolized by intestinal CYP 3A4 that have a low oral bioavailability or a narrow therapeutic index are more likely to have clinically significant interactions with grapefruit products.9 Because medications metabolized extensively by intestinal CYP 3A4 generally have low oral bioavailability, and because grapefruit inhibits this metabolic pathway, higher plasma concentrations of these medications will result. Furthermore, if the medication has a narrow therapeutic index, small increases in plasma concentration may cause drastic increases in therapeutic or adverse effects.9
When considering how to manage grapefruit-drug interactions, a physician should first decide if the interaction is clinically relevant. A number of medications (e.g., angiotensin receptor blockers, buspirone [BuSpar], estrogens, fexofenadine [Allegra], itraconazole [Sporanox], sildenafil [Viagra], triazolam [Halcion], warfarin [Coumadin]) reportedly or theoretically interact with grapefruit. However, many of these interactions have not been proven clinically significant, or inconsistent data exist.10–18 Table 19,19–30 describes medication classes that have had documented, clinically significant interactions with grapefruit products, and possible alternative therapies for these drugs.
|Drug class||Drugs potentially affected by grapefruit||Effects of interaction||Alternative treatments|
|Antiarrhythmics||Amiodarone (Cordarone), disopyramide (Norpace), quinidine||Increased plasma concentrations of amiodarone may cause thyroid or pulmonary toxicity, liver injury, QTc prolongation, proarrhythmic disorders, and bradycardia.19|
|Increased plasma concentration of quinidine and disopyramide may be cardiotoxic causing torsades de pointes.9,20|
|Calcium channel blockers||Felodipine (Plendil), nicardipine (Cardene), nifedipine (Procardia), nimodipine (Nimotop), nisoldipine (Sular)||Increased plasma concentration may lead to flushing, peripheral edema, headaches, tachycardia, symptomatic hypotension, and myocardial infarction in rare cases.9|
|Statins||Atorvastatin (Lipitor), lovastatin (Mevacor), simvastatin (Zocor)||Increased plasma concentration may cause headaches, gastrointestinal complaints, hepatic inflammation, and myopathies (e.g., rhabdomyolysis).21–24|
|Immunosuppressants||Cyclosporine (Sandimmune, Neoral), tacrolimus (Prograf)||Increased drug exposure without effects on peak concentration may cause increased adverse events or toxicity evidenced by renal toxicity, hepatic toxicity, and increased immunosuppression.25–29|
|Protease inhibitors||Saquinavir (Fortovase)||Increased plasma concentrations may cause increased side effects such as headache, fatigue, insomnia, and anxiety.30|