Grapefruit–drug interactions

The effect of grapefruit juice with regard to drug absorption was originally discovered in 1989 by a group led by pharmacologist David Bailey. Their first published clinical report on grapefruit drug interactions was in 1991. The effect was first discovered accidentally in 1989, when a test of drug interactions with alcohol used grapefruit juice to hide the taste of the ethanol. A 2005 medical review advised patients to avoid all citrus juices until further research clarifies the risks. It was reported in 2008 that similar effects had been observed with apple juice. == Polyphenols ==

Citrus fruits contain various polyphenols, which may include furanocoumarins and naringin, such as bergamottin, dihydroxybergamottin, and bergapten. Grapefruit, Seville oranges, and bergamot contain naringin. Furanocoumarins may have a stronger effect than naringin. == Mechanism ==

The effects are caused by furanocoumarins (and, to a lesser extent, flavonoids) which are compounds produced by many plants including but not limited to grapefruit. 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. Cytochrome isoforms affected by grapefruit components include CYP1A2, CYP2C9, and CYP2D6, but CYP3A4 is the major CYP enzyme in the intestine. Inhibition of enzymes can have two different effects: • Grapefruit-juice–mediated inhibition of an enzyme that metabolizes the drug to an inactive metabolite leads to excessive levels of the drug in the body. Grapefruit or grapefruit juice can reduce the absorption of many drugs by inhibiting transport across cell membranes by the transporters P-glycoprotein (a member of the superfamily of ATP-binding cassette (ABC) transporters) and members of the organo anion transporter family. These transporters appear to have a minimal effect on systemic exposure of the drugs they affect, however. 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. When larger amounts are consumed they may in addition 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). == Duration and timing ==

Metabolism interactions Grapefruit–drug interactions that affect the pre-systemic metabolism (i.e., the metabolism that occurs before the drug enters the blood) of drugs have a different duration of action than interactions that work by other mechanisms, such as on absorption, discussed below. The location of the inhibition occurs in the lining of the intestines, not within the liver. The effects last because grapefruit-mediated inhibition of drug metabolizing enzymes, like CYP3A4, is irreversible; that is, once the grapefruit has "broken" the enzyme, the intestinal cells must produce more of the enzyme to restore their capacity to metabolize drugs that the enzyme is used to metabolize. It takes around 24 hours to regain 50% of the cell's baseline enzyme activity and it can take 72 hours for the enzyme activity to completely return to baseline. For this reason, simply separating citrus consumption and medications taken daily does not avoid the drug interaction. Absorption interactions 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 four-hour interval between grapefruit consumption and the medication should suffice. 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. Because there is a growing number of medications that are known to interact with citrus, patients should consult a pharmacist or physician before consuming citrus while taking their medications. == Affected fruit ==

Grapefruit is not the only citrus fruit that can interact with medications. 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. The third approach is hampered by a paucity of knowledge of the genes in question. Furanocoumarin production has been inherited by some hybrid cultivars; others have not inherited the furanocoumarin-producing genes. A descendant of citrus cultivars that cannot produce the problematic polyphenol compounds would presumably also lack the genes to produce them. Many citrus cultivars are hybrids of a small number of ancestral species, which have now 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. In theory, cultivars in a bud sport group would be either all safe or all problematic. Nonetheless, 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. Nonetheless, many of the citrus cultivars known to be problematic seem to be closely related. Ancestral species Pomelo (the Asian fruit that 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. The Dancy cultivar has a small amount of pomelo ancestry, 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. Evidence on sweet oranges is more mixed.). Many fruits sold under these names such as Sunbursts and Murcotts are hybrids with grapefruit ancestry. Other fruit and vegetables The discovery that flavonoids are responsible for some interactions make it plausible that other fruit and vegetables are affected. Apple juice Apple juice, especially commercially produced products, interferes with the action of OATPs. This interference can decrease the absorption of a variety of commonly used medications, including beta blockers like atenolol, antibiotics like ciprofloxacin, and antihistamines like fexofenadine. Pomegranate juice Pomegranate juice inhibits the action of the drug metabolizing enzymes CYP2C9 and CYP3A4. , the currently available literature does not appear to indicate a clinically relevant impact of pomegranate juice on drugs that are metabolized by CYP2C9 and CYP3A4. == Affected drugs ==

Researchers have identified over 85 drugs with which grapefruit reacts adversely. According to a review done by the Canadian Medical Association, Incomplete list of affected drugs By enzyme Drugs that interact with grapefruit compounds at CYP3A4 include: • benzodiazepines: triazolam (Halcion), orally administered midazolam (Versed), orally administered nitrazepam (Mogodon), diazepam (Valium), clonazepam (Klonopin), alprazolam (Xanax) and quazepam (Doral, Dormalin) • ritonavir (Norvir): Inhibition of CYP3A4 prevents the metabolism of protease inhibitors such as ritonavir. • sertraline (Zoloft and Lustral) • verapamil (Covera-HS, Calan, Verelan, and Isoptin) • gilteritinib (Xospata) Drugs that interact with grapefruit compounds at CYP1A2 include: • caffeine Drugs that interact with grapefruit compounds at CYP2D6 include: • dextroamphetamine (Dexedrine) • dextroamphetamine (75%)/ levoamphetamine (25%) (Adderall) • dextromethamphetamine (Desoxyn) 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. Other interactions Additional drugs affected by grapefruit juice include, but are not limited to: • Some statins, including atorvastatin (Lipitor), lovastatin (Mevacor), and simvastatin (Zocor, Simlup, Simcor, Simvacor) • In contrast, pravastatin (Pravachol), dronedarone (Multaq), quinidine (Quinidex, Cardioquin, Quinora), disopyramide (Norpace), propafenone (Rythmol) and carvedilol (Coreg) • Acetaminophen (also known as paracetamol, brand name Tylenol) concentrations increase in the blood of mice when they consume white and pink grapefruit juice, with the white juice acting faster. "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 with a single dose of grapefruit juice, which conversely increases the efficacy and bioavailability of acetaminophen/paracetamol. • Anthelmintics: Used for treating certain parasitic infections; includes praziquantel • Buprenorphine: Metabolized into norbuprenorphine by CYP3A4 • 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. • Codeine is a prodrug that produces its analgesic properties following metabolism to morphine entirely by CYP2D6. • Ciclosporin (cyclosporine, Neoral): Blood levels of ciclosporin are increased if taken with grapefruit juice, orange juice, or apple juice. • Dihydropyridines including felodipine (Plendil), nicardipine (Cardene), nifedipine, nisoldipine (Sular) and nitrendipine (Bayotensin) • Exemestane, aromasin, and by extension all estrogen-like compounds and aromatase inhibitors that mimic estrogen in function will be increased in effect, causing increased estrogen retention and increased drug retention. • Etoposide interferes with grapefruit, orange, and apple juices. • Fluvoxamine (Luvox, Faverin, Fevarin and Dumyrox) • 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. • Ketamine: After drinking 200 mL of grapefruit juice daily for five days, the overall absorption of orally ingested ketamine was increased three-fold compared to the control group in a clinical trial. The peak blood ketamine concentration was increased over two-fold. • Levothyroxine (Eltroxin, Levoxyl, Synthroid): "Grapefruit juice may slightly delay the absorption of levothyroxine, but it seems to have only a minor effect on its bioavailability." • Losartan (Cozaar) • Omeprazole (Losec, Prilosec) • Oxycodone: Grapefruit juice enhances the exposure to oral oxycodone. In 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 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. • Quetiapine (Seroquel) • Repaglinide (Prandin) • Tamoxifen (Nolvadex): Tamoxifen is metabolized by CYP2D6 into its active metabolite 4-hydroxytamoxifen. Grapefruit juice may potentially reduce the effectiveness of tamoxifen. • Trazodone (Desyrel): Little or no interaction with grapefruit juice. • Verapamil (Calan SR, Covera HS, Isoptin SR, Verelan): atrioventricular conduction disorders. • Zolpidem (Ambien): Little or no interaction with grapefruit juice ==References==