Grapefruit–drug interactions

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Some fruit juices and fruits can inhibit enzymes that absorb and metabolize medications.

Some fruit juices and fruits can interact with numerous drugs, in many cases causing adverse effects.[1] The effect was first discovered by accident, when a test of drug interactions with alcohol used grapefruit juice to hide the taste of the ethanol.[2]

It is still best-studied with grapefruit and grapefruit juice,[1] but similar effects have more recently been seen with some (not all) other citrus fruits.[1][3][4][5][6] One medical review advises patients to avoid all citrus juices until further research clarifies the risks.[7] The interacting chemicals are found in many plants,[citation needed] and so many other foods may be affected; effects have been observed with apple juice, but their clinical significance is not yet known.[8][9][4]

Normal amounts of food and drink, such as one whole grapefruit or a small glass (200 mL (6.8 US fl oz)) of grapefruit juice, can cause drug overdose toxicity.[1] Fruit consumed three days before the medicine can still have an effect.[10] The relative risks of different types of citrus fruit have not been systematically studied.[1] Affected drugs typically have an auxiliary label saying “Do not take with grapefruit” on the container, and the interaction is elaborated on in the package insert.[11] People are also advised to ask their physician or pharmacist about drug interactions.[11]

Grapefruit Juice and Medicine May Not Mix (6774935740).jpg

The effects are caused by furanocoumarins (and, to a lesser extent, flavonoids). These chemicals inhibit key drug metabolizing enzymes, such as cytochrome P450 3A4 (CYP3A4). CYP3A4 is a metabolizing enzyme for almost 50% of drugs, and is found in the liver and small intestinal epithelial cells.[12] As a result, many drugs are affected. Inhibition of enzymes can have two different effects, depending on whether the drug is either

  1. metabolized by the enzyme to an inactive metabolite or
  2. activated by the enzyme to an active metabolite.

If the active drug is metabolized by the inhibited enzyme, then the fruit will stop the drug being metabolized, leaving elevated concentrations of the medication in the body, which can cause adverse effects.[11] Conversely, if the medication is a prodrug, it needs to be metabolised to be converted to the active drug. Compromising its metabolism lowers concentrations of the active drug, reducing its therapeutic effect, and risking therapeutic failure.

Low drug concentrations can also be caused when the fruit suppresses drug absorption from the intestine.[13]

History[edit]

The effect of grapefruit juice with regard to drug absorption was originally discovered in 1989. The first published report on grapefruit drug interactions was in 1991 in the Lancet entitled "Interactions of Citrus Juices with Felodipine and Nifedipine," and was the first reported food-drug interaction clinically. However, the effect only became well-publicized after being responsible for a number of bad interactions with medication.[14]

Active ingredients[edit]

Citrus fruits may contain a number of polyphenol compounds,[4][15] including the flavonoid naringin and furanocoumarins (such as bergamottin, dihydroxybergamottin, bergapten, and bergaptol)[citation needed]. These are natural chemicals. They may be present in all forms of the fruit, including freshly squeezed juice, frozen concentrate, and whole fruit.[citation needed]

Grapefruit, Seville oranges,[15] bergamot,[16] and possibly other citrus also contain large amounts of naringin. It can take up to 72 hours before the effects of the naringin on the CYP3A4 enzyme are seen. This is problematic as a 4 oz portion of grapefruit contains enough naringin to inhibit the metabolism of substrates of CYP3A4. Nagarin is a flavonoid which contributes to the bitter flavour of grapefruit.[6]

Fucomarins seem to have a stronger effect than nagarin under some circumstances.[17][15]

Mechanism[edit]

Organic compounds that are derivatives of furanocoumarin interfere with liver and intestinal enzyme CYP3A4 and are believed to be primarily responsible for the effects of grapefruit on the enzyme.[18] Cytochrome isoforms affected by grapefruit components also include CYP1A2, CYP2C9, and CYP2D6.[19] Bioactive compounds in grapefruit juice may also interfere with MDR1 (multidrug resistance protein 1) and OATP (organic anion transporting polypeptides), either increasing or decreasing the bioavailability of a number of drugs.[20][21][22][23][24][14] Drugs that are metabolized by these enzymes may have interactions with citrus chemicals.

When drugs are taken orally, they enter the gut lumen to be absorbed in the small intestine and sometimes, in the stomach. In order for drugs to be absorbed, they must pass through the epithelial cells that line the lumen wall before they can enter the hepatic portal circulation to be distributed systemically in blood circulation. Drugs are metabolized by drug-specific metabolizing enzymes in the epithelial cells. Metabolizing enzymes transform these drugs into metabolites. The primary purpose for drug metabolism is to detoxify, inactivate, solubilize and eliminate these drugs.[25][verification needed] As a result, the amount of the drug in its original form that reaches systemic circulation is reduced due to this first-pass metabolism.

Furanocoumarins (see section above) irreversibly inhibit a metabolizing enzyme cytochrome P450 3A4 (CYP3A4). CYP3A4 is a metabolizing enzyme for almost 50% of drugs, and is found in the liver and small intestinal epithelial cells.[12] As a result, many drugs are impacted by consumption of citrus juice. When the metabolizing enzyme is inhibited, less of the drug will be metabolized by it in the epithelial cells. A decrease in drug metabolism means more of the original form of the drug could pass unchanged to systemic blood circulation.[25][verification needed] An unexpected high dose of the drug in the blood could lead to fatal drug toxicity.[12] The CYP3A4 is located in both the liver and the enterocytes. Many oral drugs undergo first-pass (presystemic) metabolism by the enzyme. Several organic compounds (see section above) found in citrus and specifically in grapefruit juice exert inhibitory action on drug metabolism by the enzyme.

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. Citrus 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 are consumed they 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).[26] 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 MDR1 (multidrug resistance protein 1) 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.[27][better source needed][clarification needed]

Duration and timing[edit]

The effects caused by grapefruit juice last for up to 72 hours, and are greatest when the juice is ingested with the drug or up to 4 hours before the drug.[28][29][better source needed][10]

The effects last because the inhibition of the CYP3A4 enzyme is irreversible[clarification needed]. It takes around 24 hours to regain 50% of the enzyme activity and it can take 72 hours for the enzyme to completely return to activity. For this reason, simply separating citrus consumption and medication taken daily does not avoid the interaction.[12][30][31][10] For medications that interact due to inhibition of OATP (organic anion-transporting polypeptides), a relative short period of time is needed to avoid this interaction, and a 4-hour interval between grapefruit consumption and the medication should suffice.[12][27] For drugs recently sold on the market, drugs have information pages (monographs) that provide information on any potential interaction between a medication and grapefruit juice.[12] Because there is a growing number of medications that are known to interact with citrus,[1] patients should consult a pharmacist or physician before consuming citrus while taking their medications.

Affected fruit[edit]

Grapefruit is not the only citrus fruit that can interact with medications;[1][3][4][5][6] one medical review advised patients to avoid all citrus.[7]

There are three ways to test if a fruit interacts with drugs:

  1. Test a drug-fruit combination in humans[7]
  2. Test a fruit chemically for the presence of the interacting polyphenol compounds[6]
  3. Test a fruit genetically for the genes needed to make the interacting polyphenol compounds[32]

The first approach involves risk to trial volunteers. The first and second approaches have another problem: the same fruit cultivar could be tested twice with different results. Depending on growing and processing conditions, concentrations of the interacting polyphenol compounds can vary dramatically.[33][better source needed] The third approach is hampered by a paucity of knowledge of the genes in question.[32]

Citrus genetics and interactions[edit]

Citrus fruits clustered by genetic similarity of partial sequences. Most commercial citrus varieties of citrus are hybrids of the three species at the corners of the ternary diagram.[34] Fucomarin production has been inherited by some hybrid cultivars; others have not inherited the fucomarin-producing genes.

A descendant of citrus cultivars that cannot produce the problematic polyphenol compounds would presumably also lack the genes to produce them. Most citrus cultivars are hybrids of three ancestral species (see diagram; limes are a hybrid with a fourth species, not shown).[34] Unfortunately, the non-hybrid ancestral species have not been fully genetically sequenced.

Many traditional citrus groups, such as true sweet oranges and lemons, seem to be bud sports, mutant descendants of a single hybrid ancestor.[34] In theory, cultivars in a bud sport group would be either all safe or all problematic. However, new citrus varieties arriving on the market are increasingly likely to be sexually-created hybrids, not asexually-created sports.

The ancestry of a hybrid cultivar may not be known. Even if it is known, it is not possible to be certain that a cultivar will not interact with drugs on the basis of taxonomy, as it is not known which ancestors lack the capacity to make the problematic polyphenol compounds. However, many of the citrus cultivars known to be problematic seem to be closely related.

Ancestral species[edit]

Pomelo (the Asian fruit which was crossed with an orange to produce grapefruit) contains high amounts of furanocoumarin derivatives. Grapefruit relatives and other varieties of pomelo have variable amounts of furanocoumarin.[4][5][6][7]

The Dancy mandarin cultivar, which is suspected to be a true mandarin (unlike most commercial mandarins, which may be hybrids) has been tested once for furanocoumarins; none were detectable.[6]

No citron or papeda seems to have been tested.

Hybrid cultivars[edit]

Both sweet oranges and bitter oranges appear to be mandarin-pomelo hybrids,.[34] Bitter oranges (such as the Seville oranges often used in marmalade) can interfere with drugs[35] including etoposide, a chemotherapy drug, some beta blocker drugs used to treat high blood pressure, and cyclosporine, taken by transplant patients to prevent rejection of their new organs.[8] Evidence on sweet oranges is more mixed.[7]

Tests on some tangelos (hybrids of mandarins/tangerines and pomelo or grapefruit) have not shown significant amounts of furanocoumarin.[6]

Limes[clarification needed], which may or may not be pomelo descendants (but are apparently more closely related to citrons and papedas)[34] can also inhibit drug metabolism.[35]

Inaccurate labelling[edit]

Marketing classifications often do not correspond to taxonomic ones. The "Ambersweet" cultivar is classified and sold as an orange, but does not descend from the same common ancestor as sweet oranges; it has grapefruit, orange, and mandarin ancestry. Fruits are often sold as mandarin, tangerine, or satsuma (which may be synonyms[36]). Fruit sold under these names include many which are, like Sunbursts and Murcotts, hybrids with grapefruit ancestry.[37][38][5] The diversity of fruits called limes is remarkable; some, like the Spanish lime and Wild lime, are not even citrus fruit.

In some countries, citrus fruit must be labelled with the name of a registered cultivar. Juice is often not so labelled. Some medical literature also names the cultivar tested.

Other fruit and vegetables[edit]

The discovery that flavenoids are responsible for some interactions make it plausible that other fruit and vegetables are affected.[27]

Apple juice has been also implicated in interfering with etoposide, a chemotherapy drug, some beta blocker drugs used to treat high blood pressure, and cyclosporine, taken by transplant patients to prevent rejection of their new organs.[8][medical citation needed]

Affected drugs[edit]

Researchers have identified over 85 drugs with which grapefruit is known to have an adverse reaction.[39][1] According to a review done by the Canadian Medical Association,[1] there is an increase in the number of potential drugs that can interact with grapefruit juice, and of the number of fruit types that can interact with those drugs. From 2008 to 2012, the percentage of drugs known to potentially interact with citrus, with risk of harmful or even dangerous effects (gastrointestinal bleeding, nephrotoxicity), increased from 17 to 43 percent.[1]

Traits[edit]

The interaction between citrus and medication depends on the individual drug, and not the class of the drug. Drugs that interact usually share three common features: they are taken orally, normally only a small amount enters systemic blood circulation, and they are metabolized by CYP3A4.[1] However, the effects on the CYP3A4 in the liver could in principle cause interactions with non-oral drugs,[citation needed] and non-CYP3A4-meditated effects also exist.[27]

Cytochrome isoforms affected by grapefruit components include CYP3A4, CYP1A2, CYP2C9, and CYP2D6.[19] Drugs that are metabolized by these enzymes may have interactions with components of grapefruit.

An easy way to tell if a medication may be affected by grapefruit juice is by researching whether another known CYP3A4 inhibitor drug is already contraindicated with the active drug of the medication in question. Examples of such known CYP3A4 inhibitors include cisapride (Propulsid),[citation needed] erythromycin, itraconazole (Sporanox), ketoconazole (Nizoral), and mibefradil (Posicor).[40]

Incomplete list of affected drugs[edit]

By enzyme[edit]

Drugs that interact with grapefruit compounds at CYP3A4 include:

Drugs that interact with grapefruit compounds at CYP1A2 include:

Drugs that interact with grapefruit compounds at CYP2D6 include:

Other stimulants that interact with the CYP2D6 enzyme include:

Research has been done on the interaction between amphetamines and CYP2D6 enzyme, and researchers concluded that some parts of substrate molecules contribute to the binding of the enzyme.[50]

Other interactions[edit]

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

  • Some statins, including atorvastatin (Lipitor),[51] lovastatin (Mevacor) and simvastatin (Zocor, Simlup, Simcor, Simvacor)[52]
  • Anti-arrhythmics including amiodarone (Cordarone), dronedarone (Multaq), quinidine (Quinidex, Cardioquin, Quinora), disopyramide (Norpace), propafenone (Rythmol) and carvedilol (Coreg)[53]
  • 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)[53]
  • Erectile dysfunction drugs sildenafil (Viagra), tadalafil (Cialis) and vardenafil (Levitra)[52][54]
  • Acetaminophen/paracetamol (Tylenol) concentrations were found to be increased in murinae blood by white and pink grapefruit juice, with the white juice acting faster.[55] Interestingly, "the bioavailability of paracetamol was significantly reduced following multiple GFJ administration" in mice and rats. This suggests that repeated intake of grapefruit juice reduces the efficacy and bioavailability of acetaminophen/paracetamol in comparison to a single dose of grapefruit juice which conversely increases the efficacy and bioavailability of acetaminophen/paracetamol.[56][57]
  • Anthelmintics: Used for treating certain parasitic infections; includes praziquantel
  • Apremilast (Otezla): Used to treat psoriasis.[58][59][not in citation given]
  • Buprenorphine: Metabolized into norbuprenorphine by CYP3A4[60]
  • 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.[61]
  • Codeine is a prodrug that produces its analgesic properties following metabolism to morphine entirely by CYP2D6.[62]
  • Ciclosporin (cyclosporine, Neoral): Blood levels of ciclosporin are increased if taken with grapefruit juice, orange juice, or apple juice.[8] A plausible mechanism involves the combined inhibition of enteric CYP3A4 and MDR1, 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.[63]
  • Dihydropyridines including felodipine (Plendil), nicardipine (Cardene), nifedipine, nisoldipine (Sular) and nitrendipine (Bayotensin)[52]
  • Erlotinib (Tarceva) [64]
  • 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.[65]
  • Etoposide interferes with grapefruit, orange, and apple juices.[8]
  • Fexofenadine (Allegra)[66][67]
  • Fluvoxamine (Luvox, Faverin, Fevarin and Dumyrox)[68]
  • 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 MDR1 when taken concomitantly with ciclosporin.[69]
  • Lamotrigine[citation needed]
  • Levothyroxine (Eltroxin, Levoxyl, Synthroid): the absorption of levothyroxine is affected by grapefruit juice.[clarification needed][70]
  • Losartan (Cozaar)[53]
  • Methadone: Inhibits the metabolism of methadone and raises serum levels.[71]
  • Omeprazole (Losec, Prilosec)[72]
  • 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.[73]
  • Quetiapine (Seroquel)[74]
  • Repaglinide (Prandin)[53]
  • Tamoxifen (Nolvadex): Tamoxifen is metabolized by CYP2D6 into its active metabolite 4-hydroxytamoxifen. Grapefruit juice may potentially reduce the effectiveness of tamoxifen.[75]
  • Trazodone (Desyrel): Little or no interaction with grapefruit juice.[76]
  • Verapamil (Calan SR, Covera HS, Isoptin SR, Verelan)[53]
  • Warfarin (coumadin)[77]
  • Zolpidem (Ambien): Little or no interaction with grapefruit juice.[76]
Drugs affected by grapefruit juice[35]
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)
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 ethinylestradiol (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)[78]
ivabradine (Corlanor)[79]

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