grapefruit–drug interactions grapefruit–drug interactions some fruit juices and fruits can interact with numerous drugs, in many cases causing adverse effects. the effect is most studied with grapefruit and grapefruit juice, but similar effects have been observed with certain other citrus fruits. the effect was first discovered accidentally in 1991, 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. one whole grapefruit, or a small glass (200 ml, 6.8 us fl oz) of grapefruit juice, can cause drug overdose toxicity. fruit consumed three days before the medicine can still have an effect. the relative risks of different types of citrus fruit have not been systematically studied. affected drugs typically have an auxiliary label saying "do not take with grapefruit" on the container, and the interaction is elaborated upon in the package insert. people are also advised to ask their physician or pharmacist about drug interactions. 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. as a result, many drugs are affected. inhibition of enzymes can have two different effects, depending on whether the drug is either metabolized by the enzyme to an inactive metabolite, or activated by the enzyme to an active metabolite. in the first instance, inhibition of drug-metabolizing enzymes results in elevated concentrations of an active drug in the body, which may cause adverse effects. 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. history the effect of grapefruit juice with regard to drug absorption was originally discovered in 1989. the first published clinical report on grapefruit drug interactions was in 1991 in the lancet entitled "interactions of citrus juices with felodipine and nifedipine." polyphenols citrus fruits may contain various polyphenols, including naringin and furanocoumarins, such as bergamottin, dihydroxybergamottin, and bergapten. grapefruit, seville oranges, and bergamot contain naringin. furanocoumarins may have a stronger effect than naringin. mechanism organic derivatives of furanocoumarin interfere with liver and intestinal enzyme cyp3a4 and may be responsible for the effects of grapefruit on the enzyme. cytochrome isoforms affected by grapefruit components also include cyp1a2, cyp2c9, and cyp2d6. drugs 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. as a result, the amount of the drug in its original form that reaches systemic circulation is reduced due to this first-pass metabolism. 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. 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 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). 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 multidrug resistance-associated protein 2 localized in the brush border of the enterocytes. 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 interaction is greatest when the juice is ingested with the drug or up to 4 hours before the drug. 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 4-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. one medical review advised patients to avoid all citrus. there are three ways to test if a fruit interacts with drugs: test a drug–fruit combination in humans test a fruit chemically for the presence of the interacting polyphenol compounds test a fruit genetically for the genes needed to make the interacting polyphenol compounds 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. citrus genetics and interactions citrus fruits clustered by genetic similarity. most commercial varieties of citrus are hybrids of the three species at the corners of the ternary diagram, and genetically distinct hybrids often bear the same common name. 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. 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, but is genetically close to a non-hybrid true mandarin (unlike most commercial mandarins, which may have much more extensive hybridization). eight dancy fruits, all picked at one time from one tree, have been blended and tested for furanocoumarins; none were detectable. no citron or papeda seems to have been tested. hybrid cultivars both sweet oranges and bitter oranges are mandarin-pomelo hybrids. bitter oranges (such as the seville oranges often used in marmalade) can interfere with drugs 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. tests on some tangelos (hybrids of mandarins/tangerines and pomelo or grapefruit) have not shown significant amounts of furanocoumarin; these studies were also conducted on eight fruit all picked at one time from one tree. common lemons are the product of orange/citron hybridization, and hence have pomelo ancestry, and although key limes are papeda/citron hybrids, the more commercially prevalent persian limes and similar varieties are crosses of the key lime with lemons, and hence likewise have pomelo ancestry. these limes can also inhibit drug metabolism. other less-common citrus species also referred to as lemons or limes are genetically distinct from the more common varieties, with different proportions of pomelo ancestry. inaccurate labeling 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). fruit sold under these names include many that are, like sunbursts and murcotts, hybrids with grapefruit ancestry. 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 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 montelukast. apple juice has been implicated in interfering with etoposide, a chemotherapy drug, and cyclosporine, taken by transplant patients to prevent rejection of their new organs. pomegranate juice pomegranate juice inhibits the action of the drug metabolizing enzymes cyp2c9 and cyp3a4. as of 2014, however, 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 is known to have an adverse reaction. 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, and of the number of fruit types that can interact with those drugs. from 2008 to 2012, the number of drugs known to potentially interact with grapefruit, with risk of harmful or even dangerous effects (gastrointestinal bleeding, nephrotoxicity), increased from 17 to 43. traits 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. the effects on the cyp3a4 in the liver could in principle cause interactions with non-oral drugs, and non-cyp3a4-mediated effects also exist. cytochrome isoforms affected by grapefruit components include cyp3a4, cyp1a2, cyp2c9, and cyp2d6. 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