Grapefruit–drug interactions

Pink grapefruit

Grapefruit and grapefruit juice have been found to interact with numerous drugs, in many cases resulting in adverse effects.^[1] Some other citrus fruits can have similar effects;^{[1][2][3][4][5]} one medical review advised patients to avoid all citrus.^[6]

The furanocoumarins (and to a lesser extent the flavonoids) are responsible for the effects. These active materials inhibit a key enzyme (cytochrome P450 isoform CYP3A4) which is responsible (among other activities) to drug metabolism. The effect happens in two ways. One is that grapefruit can block the hepatic CYP3A4 thereby affecting the medication metabolism.^[7] If the drug is not metabolized, then the level of the drug in the blood can become too high, leading to an adverse effect.^[7] On the other hand, if the medication is provided as a pro-drug, compromising its metabolism may prevent the drug from being created, thereby reducing its therapeutic effect. The other effect is that grapefruit can block the enterocyte CYP3A4 thereby affecting the medication absorption in the intestine.^[7] If the medication is absorbed to a lesser extent, it may not reach a therapeutic level and its effect may be compromised.^[7]

One whole grapefruit or a glass of 200 mL (6.8 US fl oz) of grapefruit juice can cause drug overdose toxicity.^[8] Drugs which are incompatible with grapefruit are typically labeled on the container or package insert.^[7] People taking drugs can ask their health care provider or pharmacist questions about grapefruit/drug interactions.^[7]

Active ingredients

Grapefruit contains a number of polyphenolic compounds, including the flavanone naringin, alongside the two furanocoumarins, bergamottin and dihydroxybergamottin. 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.^[9] 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.^{[10][11][12][13][14][15]}

The furanocoumarins found in grapefruit juice are natural chemicals. Thus, they are present in all forms of the fruit, including freshly squeezed juice, frozen concentrate, and whole fruit. All these forms of the grapefruit juice have the potential to limit the metabolizing activity of CYP3A4. One whole grapefruit, or a glass of 200 mL (6.8 US fl oz) of grapefruit juice can cause drug overdose toxicity.^[16][17]

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.^[3][4][5][6]

Mechanism

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.^[18]

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).^[19] 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.^[20][21][22]

Furanocoumarins irreversibly inhibit a cytochrome P450 metabolizing enzyme called CYP3A4. CYP3A4 is a metabolizing enzyme for almost 50% of drugs, and is found in the liver and small intestinal epithelial cells.^[23] As a result, many drugs are impacted by consumption of grapefruit 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.^[24] An unexpected high dose of the drug in the blood could lead to fatal drug toxicity.^[23]

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.^[24] As a result, the amount of the drug in its original form that reaches systemic circulation is reduced due to this first-pass metabolism.

Duration

Inhibition of the CYP3A4 enzyme is irreversible and lasts a significant period of time. 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 grapefruit consumption and medication taken daily does not avoid the interaction.^{[25][26][27][28]} 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. A 4-hour interval between grapefruit consumption and the medication should suffice.^[25] 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.^[23] Because there is a growing number of medications that are known to interact with grapefruit juice,^[16] patients should consult a pharmacist or physician before planning to take grapefruit juice with their medications.

Affected drugs

The interaction between grapefruit juice and other medication depends on the individual drug, and not the class of the drug. Drugs that interact with grapefruit juice share 3 common features: they are taken orally, normally only a small amount enters systemic blood circulation, and they are metabolized by CYP3A4.^[16]

Grapefruit can have a number of interactions with drugs. Researchers have identified 85 drugs with which grapefruit is known to have an adverse reaction.^[29] According to a review done by the Canadian Medical Association, there is an increase in the number of potential drugs that can interact with grapefruit juice. From 2008 to 2012, the percentage of drugs known to potentially interact with grapefruit juice, with risk of harmful or even dangerous effects (gastrointestinal bleeding, nephrotoxicity), increased from 17 to 43 percent.^[16][17]

Cytochrome isoforms affected by grapefruit components include CYP3A4, CYP1A2, CYP2C9, and CYP2D6.^[30] 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), erythromycin, itraconazole (Sporanox), ketoconazole (Nizoral),and mibefradil (Posicor).^[31]

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

• The benzodiazepines triazolam (Halcion), orally administered midazolam (Versed), orally administered nitrazepam (Mogodon), diazepam (Valium), alprazolam (Xanax) and quazepam (Doral, Dormalin)^[32]
• certain amphetamines: dextroamphetamine and levoamphetamine (Dexedrine, Adderall)^[33]
• ritonavir (Norvir): Inhibition of CYP3A4 prevents the metabolism of protease inhibitors such as ritonavir.^[34]
• sertraline (Zoloft and Lustral)^[35]

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

• Caffeine^[36]

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

• dextroamphetamine (Dexedrine)^[33]
• levoamphetamine (Adderall)^[37]
• methamphetamine (Desoxyn)^[38]

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

• methylphenidate (Ritalin, Concerta)^[39]

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.^[40]

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

• Some statins, including atorvastatin (Lipitor),^[41] lovastatin (Mevacor) and simvastatin (Zocor, Simlup, Simcor, Simvacor)^[42]
  • (In contrast, pravastatin^[41] (Pravachol), fluvastatin (Lescol) and rosuvastatin (Crestor)^[42] are unaffected by grapefruit.)
• Anti-arrhythmics including amiodarone (Cordarone), dronedarone (Multaq), quinidine (Quinidex, Cardioquin, Quinora), disopyramide (Norpace), propafenone (Rythmol) and carvedilol (Coreg)^[43]
• 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)^[43]
• Erectile dysfunction drugs sildenafil (Viagra), tadalafil (Cialis) and vardenafil (Levitra)^[42][44]
• Acetaminophen/paracetamol (Tylenol) concentrations were found to be increased in murine blood by white and pink grapefruit juice, with the white juice acting faster.^[45] 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.^[46][47]
• Anthelmintics: Used for treating certain parasitic infections; includes praziquantel
• Apremilast (Otezla): Used to treat psoriasis.^[48][49]
• Buprenorphine: Metabolized into norbuprenorphine by cytochrome-P450 isoenzyme 3A4^[50]
• 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.^[51]
• Codeine is a prodrug that produces its analgesic properties following metabolism to morphine entirely by the cytochrome P450 isoform CYP2D6.^[52] 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.^[53]
• Dihydropyridines including felodipine (Plendil), nicardipine (Cardene), nifedipine, nisoldipine (Sular) and nitrendipine (Bayotensin)^[42]
• Erlotinib (Tarceva) ^[54]
• 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.^[55]
• Fexofenadine (Allegra)^[56][57]
• Fluvoxamine (Luvox, Faverin, Fevarin and Dumyrox)^[58]
• 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.^[59]
• Lamotrigine
• Levothyroxine (Eltroxin, Levoxyl, Synthroid): the absorption of levothyroxine is affected by grapefruit juice.^[60]
• Losartan (Cozaar)^[43]
• Methadone: Inhibits the metabolism of methadone and raises serum levels.^[61]
• Omeprazole (Losec, Prilosec)^[62]
• 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.^[63]
• Quetiapine (Seroquel)^[64]
• Repaglinide (Prandin)^[43]
• Tamoxifen (Nolvadex): Tamoxifen is metabolized by CYP2D6 into its active metabolite 4-hydroxytamoxifen. Grapefruit juice may potentially reduce the effectiveness of tamoxifen.^[65]
• Trazodone (Desyrel): Little or no interaction with grapefruit juice.^[66]
• Verapamil (Calan SR, Covera HS, Isoptin SR, Verelan)^[43]
• Warfarin (coumadin)^[67]
• Zolpidem (Ambien): Little or no interaction with grapefruit juice.^[66]

Society and culture

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.^[15]

Similar effects

Grapefruit juice may be the first drug-interacting fruit juice documented, but apple and orange juices have 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.^[70] Unlike other fruits, grapefruit contains a large amount of naringin, and 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.

Juice of limes and Seville oranges can also inhibit drug metabolism, however, as can apple juice with some drugs.^[68]

References