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Grapefruit–drug interactions

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Pink grapefruit

Grapefruit and grapefruit juice have been found to interact with numerous drugs (at least 85 known by 2013), in many cases resulting in adverse effects.[1] Organic compounds that are furanocoumarin derivatives interfere with the hepatic and intestinal enzyme cytochrome P450 isoform CYP3A4 and are believed to be primarily responsible for the effects of grapefruit on the enzyme. Bioactive compounds in grapefruit juice may also interfere with P-glycoprotein and organic anion transporting polypeptides (OATPs), either increasing or decreasing the bioavailability of a number of drugs. Pomelo (the Asian fruit which was crossed with an orange to produce grapefruit) also contains high amounts of furanocoumarin derivatives. Grapefruit relatives and other pomelo descendants have variable amounts of furanocoumarins.[2][3]

Affected drugs

Cytochrome isoforms affected by grapefruit components include CYP3A4, CYP1A2, CYP2C9, and CYP2D6.[4] Drugs that are metabolized by these enzymes may have interactions with components of grapefruit.

Drugs that interact with grapefruit compounds at the cytochrome P450 CYP3A4 isoform include:

Drugs that interact with grapefruit compounds at the cytochrome P450 CYP1A2 isoform include:

Drugs that interact with grapefruit compounds at the cytochrome P450 CYP2D6 isoform include:

Other stimulants that interact with the cytochrome P450 CYP2D6 enzyme include:

Research has been done on the interaction between amphetamines and the cytochrome P450 CYP2D6 enzyme, and researchers concluded that some parts of substrate molecules contribute to the binding of the enzyme.[12]

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

  • Some statins, including atorvastatin (Lipitor),[13] lovastatin (Mevacor) and simvastatin (Zocor, Simlup, Simcor, Simvacor)[14]
  • Anti-arrhythmics including amiodarone (Cordarone), dronedarone (Multaq), quinidine (Quinidex, Cardioquin, Quinora), disopyramide (Norpace), propafenone (Rythmol) and carvedilol (Coreg)[15]
  • Amlodipine: Grapefruit increases the available amount of the drug in the blood stream, leading to an unpredictable increase in antihypertensive effects.
  • Anti-migraine drugs ergotamine (Cafergot, Ergomar), amitriptyline (Elavil, Endep, Vanatrip) and nimodipine (Nimotop)[15]
  • Erectile dysfunction drugs sildenafil (Viagra), tadalafil (Cialis) and vardenafil (Levitra)[14][16]
  • Acetaminophen/paracetamol (Tylenol) concentrations were found to be increased in murine blood by white and pink grapefruit juice, with the white juice acting faster.[17]
  • Anthelmintics: Used for treating certain parasitic infections; includes praziquantel
  • Apremilast (Otezla): Used to treat psoriasis.[18][19][failed verification]
  • Buprenorphine: Metabolized into norbuprenorphine by cytochrome-P450 isoenzyme 3A4[20]
  • Buspirone (Buspar): Grapefruit juice increased peak and AUC plasma concentrations of buspirone 4.3- and 9.2-fold, respectively, in a randomized, 2-phase, ten-subject crossover study.[21]
  • Codeine is a prodrug that produces it's analgesic properties following metabolism to morphine entirely by the cytochrome P450 isoform CYP2D6.[22] Because components in grapefruit juice interfere with the CYP2D6 isoform, preventing metabolism of codeine to morphine, consuming grapefruit juice greatly reduces the analgesic properties of codeine.
  • Ciclosporin (Neoral): Blood levels of ciclosporin 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 (e.g., nephrotoxicity). Blood levels of tacrolimus (Prograf) can also be equally affected for the same reason as ciclosporin, as both drugs are calcineurin inhibitors.[23]
  • Dihydropyridines including felodipine (Plendil), nicardipine (Cardene), nifedipine, nisoldipine (Sular) and nitrendipine (Bayotensin)[14]
  • Duloxetine (Cymbalta): May increase the risk of Serotonin Syndrome [24][25]
  • Erlotinib (Tarceva) [26]
  • Exemestane, aromasin, and by extension all estrogen-like compounds and aromatase inhibitors which mimic estrogen in function will be increased in effect, causing increased estrogen retention and increased drug retention.[27]
  • Fexofenadine (Allegra)[28]
  • Fluvoxamine (Luvox, Faverin, Fevarin and Dumyrox)[29]
  • Imatinib (Gleevec): Although no formal studies with imatinib and grapefruit juice have been conducted, the fact that grapefruit juice is a known inhibitor of the CYP 3A4 suggests that co-administration may lead to increased imatinib plasma concentrations. Likewise, although no formal studies were conducted, co-administration of imatinib with another specific type of citrus juice called Seville orange juice (SOJ) may lead to increased imatinib plasma concentrations via inhibition of the CYP3A isoenzymes. Seville orange juice is not usually consumed as a juice because of its sour taste, but it is found in marmalade and other jams. Seville orange juice has been reported to be a possible inhibitor of CYP3A enzymes without affecting P-glycoprotein when taken concomitantly with ciclosporin.[30]
  • Lamotrigine
  • Levothyroxine (Eltroxin, Levoxyl, Synthroid): the absorption of levothyroxine is affected by grapefruit juice.[clarification needed][31]
  • Losartan (Cozaar)[15]
  • Methadone: Inhibits the metabolism of methadone and raises serum levels.[32]
  • Omeprazole (Losec, Prilosec)[33]
  • Oxycodone: grapefruit juice enhances the exposure to oral oxycodone. And a randomized, controlled trial 12 healthy volunteers ingested 200 mL of either grapefruit juice or water three times daily for five days. On the fourth day 10 mg of oxycodone hydrochloride were administered orally. Analgesic and behavioral effects were reported for 12 hours and plasma samples were analyzed for oxycodone metabolites for 48 hours. Grapefruit juice and increased the mean area under the oxycodone concentration-time curve (AUC(0-∞)) by 1.7 fold, the peak plasma concentration by 1.5-fold and the half-life of oxycodone by 1.2-fold as compared to water. The metabolite-to-parent ratios of noroxycodone and noroxymorphone decreased by 44% and 45% respectively. Oxymorphone AUC(0-∞) increased by 1.6-fold but the metabolite-to-parent ratio remained unchanged.[34]
  • Quetiapine (Seroquel)[35]
  • Repaglinide (Prandin)[15]
  • Tamoxifen (Nolvadex): Tamoxifen is metabolized by CYP2D6 into its active metabolite 4-hydroxytamoxifen. Grapefruit juice may potentially reduce the effectiveness of tamoxifen.[36]
  • Trazodone (Desyrel): Little or no interaction with grapefruit juice.[37]
  • Verapamil (Calan SR, Covera HS, Isoptin SR, Verelan)[15]
  • Warfarin (coumadin)[38]
  • Zolpidem (Ambien): Little or no interaction with grapefruit juice.[37]

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.[39]

The list of active furanocoumarins found in grapefruit juice includes bergamottin, bergapten, bergaptol and 6',7'-dihydroxybergamottin. Another inhibitor of cytochrome P450 enzymes is naringin.

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 effect and toxicity. Grapefruit juice inhibits the enzyme only within the intestines if consumed in small amounts. Intestinal enzyme inhibition will only affect the potency of orally administrated drugs. When larger amounts of grapefruit are consumed it may also inhibit the enzyme in the liver. The hepatic enzyme inhibition may cause an additional increase in potency and a prolonged metabolic half-life (prolonged metabolic half-life for all ways of drug administration).[40] The degree of the effect varies widely between individuals and between samples of juice, and therefore 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 72 hours, and its effect is the greatest when the juice is ingested with the drug or up to 4 hours before the drug.[41][42][43]

Drugs affected by grapefruit juice[44]
Drug class Major Interactions Minor interactions
Antiarrhythmic agents amiodarone (Cordarone)
dronedarone (Multaq)
Antihistamines terfenadine (Seldane) (off the market)
diphenhydramine (Benadryl) (partially)
astemizole (Hismanal) (off the market)
Calcium channel antagonists felodipine (Plendil)
nicardipine (Cardene)
nifedipine (Procardia)
nimodipine (Nimotop)
nisoldipine (Sular)
isradipine (DynaCirc)
Cholesterol-lowering drugs aka
Statins (HMG-CoA reductase inhibitors)		 simvastatin (Zocor)
lovastatin (Mevacor)		 atorvastatin (Lipitor)
cerivastatin (Baycol) (off the market)
Cough Suppressant/NMDA Antagonist dextromethorphan
Erectile dysfunction drugs sildenafil (Viagra)
tadalafil (Cialis)
vardenafil (Levitra)
HIV protease inhibitors saquinavir (Invirase)
ritonavir (Norvir)
nelfinavir (Viracept)
amprenavir (Agenerase)
Hormones ethinyl estradiol (Ortho-Cept, many others)
methylprednisolone (Medrol)
Immunosuppressants ciclosporin (Sandimmune Neoral)
tacrolimus (Prograf)
sirolimus (Rapamune)
mercaptopurine
Sedatives, hypnotics, and anxiolytics buspirone (Buspar) triazolam (Halcion)
midazolam (Versed)
diazepam (Valium)
zaleplon (Sonata)
alprazolam (Xanax)
Other psychotropics carbamazepine (Tegretol)
trazodone (Desyrel)
quetiapine (Seroquel)
fluvoxamine (Luvox)
nefazodone (Serzone)
Other miscellaneous drugs cisapride (Prepulsid, Propulsid)[45]

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External links

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