List of drugs affected by grapefruit

File:Citrus paradisi (Grapefruit, pink) white bg.jpg

Sliced pink grapefruit

Grapefruit and grapefruit juice have the potential to interact with numerous drugs. A number of organic compounds, identified as furanocoumarin derivates, interfere with the hepatic and intestinal enzyme cytochrome P450 isoform CYP3A4 and are therefore primarily responsible for the interaction. However, bioactive compounds in grapefruit juice may also interfere with P-glycoprotein and organic anion transporting polypeptides (OATPs) either increasing or decreasing bioavailability of a number of drugs.

History

In 1989 a pharmacological study evaluated the possibility of an interaction between ethanol ingestion and medication with the dihydropyridine calcium channel blocker - felodipine. Grapefruit juice was used as a flavouring additive during the test. The results of study showed several-fold increase of felodipine concentrations compared to results obtained in other investigations of the drug. Additionally, there were lower blood pressure readings and more adverse effects compared to the group of subjects on felodipine alone. Further investigations revealed that grapefruit juice strikingly elevated felodipine bioavailability and could influence its other pharmacokinetic and pharmacodynamic properties.

Affected drugs

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The following drugs are affected by CYP3A4 inhibition with grapefruit compounds:

• The benzodiazepines triazolam, midazolam, alprazolam and quazepam
• Ritonavir inhibits CYP3A4 preventing the metabolism of protease inhibitors

Additional drugs found to be affected by grapefruit juice include, but are not limited to:

• Statins such as atorvastatin, lovastatin, and simvastatin with the exception of Pravastatin which is unaffected.
• Dihydropyridines including felodipine (Plendil), nicardipine (Cardene), difedipine, nisoldipine (Sular), nitrendipine (Bayotensin)
• losartan (Cozaar)
• The cough suppressant dextromethorphan
• repaglinide (Prandin)
• verapamil (Calan SR, Covera HS, Isoptin SR, Verelan)
• buspirone
• Antiarrhythmics including amiodarone (Cordarone), dronedarone (Multaq), quinidine (Quinidex, Cardioquin, Quinora), disopyramide (Norpace), propafenone (Rhythmol), and carvedilol
• Antihistaminic terfenadine
• Cisapride (which treats GERD)
• The male impotence drugs sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra)
• The anti-migraine drugs ergotamine (Cafergot, Ergomar) and nimodipine (Nimotop)
• Fluvoxamine (Luvox, Faverin, Fevarin and Dumyrox)
• Codeine and Tramadol. It reduces the amount of codeine converted by CYP3A4 into norcodeine thus increasing the amount metabolised into morphine. Morphine itself, however, is not affected by grapefruit juice, as it is not metabolised by the cytochrome P450 system.
• Cyclosporine. Blood levels of cyclosporine are increased if taken with grapefruit juice. A plausible mechanism involves the combined inhibition of enteric CYP3A4 and P-glycoprotein, which potentially leads to serious adverse events (eg, nephrotoxicity).Blood levels of Prograf [Tacrolimus] can also be equally affected for the same reason as it does with Cyclosporine [both drugs are in the Calcineurin Inhibitor family]
• Omeprazole
• Zolpidem (Ambien) Increased effect.
• Oxycodone (Oxycodone is metabolized by the cytochrome P450 system, specifically CYP3A4, of which the bergamottin flavonoid is a strong inhibitor)
• Quetiapine (Seroquel, Ketipinor)
• Methadone Inhibits the metabolism of methadone and raises serum levels.
• Buprenorphine Metabolized into norbuprenorphine by cytochrome-P450 isoenzyme 3A4
• Marijuana Oral ingestion
• Psilocybin
• Trazodone (Desyrel) Reports have indicated users experiencing little to no effect.
• Anthelmintics (Used for treating certain parasitic infections, includes Praziquantel Albendazole Mebendazole)
• Slow release versions of drugs are affected by grapefruit, causing the entire dosage to be metabolized at once.
• Carbamazepine (Tegretol) Grapefruit or grapefruit juice slows the breakdown of this drug, increasing the level of it in blood

Mechanism of the interaction

The CYP3A4 isoform of cytochrome P450 is located in both the liver and the enterocytes. Many oral drugs undergo first-pass (presystemic) metabolism by the enzyme. Several organic compounds found in grapefruit and specifically in grapefruit juice exert inhibitory action on drug metabolism by the enzyme. It has been established that a group of compounds called furanocoumarins are responsible for this interaction and not flavonoids as was previously reported. The list of active furanocoumarins found in grapefruit juice includes: bergamottin, bergapten, bergaptol and 6',7'-dihydroxybergamottin.

This interaction is particularly dangerous when the drug in question has a low therapeutic index, so that a small increase in blood concentration can be the difference between therapeutic success and toxicity. Grapefruit juice only inhibits the enzyme within the intestines, not in the liver or elsewhere in the body, and does not impact injected drugs. The degree of the effect varies widely between individuals and between samples of juice, therefore it cannot be accounted for a priori.

Another mechanism of interaction is possibly through the P-glycoprotein (Pgp) that is localized in the apical brush border of the enterocytes. Pgp transports lipophilic molecules out of the enterocyte back into the intestinal lumen. Drugs that possess lipophilic properties are either metabolised by CYP3A4 or removed into the intestine by the Pgp transporter. Both the Pgp and CYP3A4 may act synergistically as a barrier to many orally administered drugs. Therefore their inhibition (both or alone) can markedly increase the bioavailability of a drug.

The interaction caused by grapefruit compounds lasts for up to 24 hours and its effect is the greatest when the juice is ingested with the drug or up to 4 hours before the drug.

The flavonoid existing in highest concentration in grapefruit juice is naringin, which in humans is metabolised to naringenin. Other flavonoids exist in grapefruit juice in lower concentrations as well. Orange juice does not contain naringin in as high a concentration, instead containing hesperetin. It is sometimes recommended as a substitute. Juice of limes and Seville oranges can also inhibit drug metabolism, however, as can apple juice with some drugs.

Drugs affected by grapefruit juice

Drug class	Major Interactions	Minor interactions
Calcium channel antagonists		Plendil Cardene (Nicardipine) Procardia (Nifedipine) Nimotop Sular DynaCirc
Antiarrhythmics	Cordarone Multaq
Statins (HMG-CoA reductase inhibitors)	Mevacor (Lovastatin)	Lipitor Baycol (off the market)
Immunosuppressants		Sandimmune (Cyclosporine) Prograf Rapamune Mercaptopurine
Dissociatives	Dextromethorphan
Sedatives, hypnotics, and anxiolytics	Buspar	Halcion Versed Valium (Diazepam) Sonata (Zaleplon) Alprazolam
Other psychotropics		Tegretol (Carbamazepine) Desyrel Serzone Seroquel Fluvoxamine
Antihistamines	Seldane (off the market) Hismanal (off the market)	Claritin (Loratadine)
HIV protease inhibitors		Invirase Norvir Viracept Agenerase
Hormones		Ortho-Cept (Ethinyl estradiol) Depo-Medrol (Methylprednisolone)
Other drugs		Viagra Propulsid