Some fruit juices and fruits can interact with numerous drugs, in many cases causing adverse effects. [1] The effect is most studied with grapefruit and grapefruit juice, [1] but similar effects have been observed with certain other citrus fruits. [1] [2] [3] [4]
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. [5] 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 upon in the package insert. [6] People are also advised to ask their physician or pharmacist about drug interactions. [6] However, some experts believe that for the majority of patients, complete avoidance of grapefruit is unwarranted. [7]
Although a prospective cohort study of middle-aged women indicated that some flavonoid-rich foods are associated with a reduction in all-cause mortality, frequent grapefruit consumption was associated with a small increase in all-cause mortality, possibly because of the clinically significant drug interactions of the non-flavonoid components. [8]
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. [9] 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. [9] [10] A 2005 medical review advised patients to avoid all citrus juices until further research clarifies the risks. [11] It was reported in 2008 that similar effects had been observed with apple juice. [2] [12] [13]
Citrus fruits may contain various polyphenols, including furanocoumarins and naringin, such as bergamottin, dihydroxybergamottin, and bergapten. [14] Grapefruit, Seville oranges, [15] and bergamot [16] contain naringin. Furanocoumarins may have a stronger effect than naringin. [15] [17]
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. [18] 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. [19] Organic derivatives of furanocoumarin interfere with liver and intestinal enzyme CYP3A4 and may be responsible for the effects of grapefruit on the enzyme. [20] Cytochrome isoforms affected by grapefruit components also include CYP1A2, CYP2C9, and CYP2D6, [21] [22] [23] [24] [25] but CYP3A4 is the major CYP enzyme in the intestine. [26]
Inhibition of enzymes can have two different effects, depending on whether the drug is either
Grapefruit or grapefruit juice can also 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. [26] [7] These transporters appear to have a minimal effect on systemic exposure of the drugs they affect, however. [7] Many drugs are affected by consumption of citrus juice. When the metabolizing enzyme is inhibited, less of the drug will be metabolized by it in the epithelial cells. [19] 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). [28]
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. [19]
The interaction is greatest when the juice is ingested with the drug or up to 4 hours before the drug. [1] [5] [29]
The location of the inhibition occurs in the lining of the intestines, not within the liver. [30] The effects last because grapefruit-mediated inhibition of drug metabolizing enzymes, like CYP3A4, is irreversible; [30] 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. [19] 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. [5]
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. [19] [31] 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. [19] 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.
Grapefruit is not the only citrus fruit that can interact with medications. [1] [2] [3] [4] One medical review advised patients to avoid all citrus. [11]
There are three ways to test if a fruit interacts with drugs:
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. [32]
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. [33] [34]
Many traditional citrus groups, such as true sweet oranges and lemons, seem to be bud sports, mutant descendants of a single hybrid ancestor. [35] 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.
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. [11] [2] [36] [37]
The Dancy cultivar has a small amount of pomelo ancestry, [34] 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. [36]
Both sweet oranges and bitter oranges are mandarin-pomelo hybrids. [34] [35] Bitter oranges (such as the Seville oranges often used in marmalade) can interfere with drugs [38] 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. [12] Evidence on sweet oranges is more mixed. [11]
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. [36]
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. [33] [34] These limes can also inhibit drug metabolism. [38] 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. [33]
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 [39] ). Fruit sold under these names include many that are, like Sunbursts and Murcotts, hybrids with grapefruit ancestry. [36] [40] [41]
The discovery that flavonoids are responsible for some interactions make it plausible that other fruit and vegetables are affected. [31]
Apple juice, especially commercially produced products, interferes with the action of OATPs. [42] 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. [42] [43]
Pomegranate juice inhibits the action of the drug metabolizing enzymes CYP2C9 and CYP3A4. [44] As of 2014 [update] , 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. [44]
Researchers have identified over 85 drugs with which grapefruit is known to have an adverse reaction. [45] [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 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. [1]
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] The effects on the CYP3A4 in the liver could, in principle, cause interactions with non-oral drugs,[ citation needed ] and non-CYP3A4-mediated effects also exist. [31]
Cytochrome isoforms affected by grapefruit components include CYP3A4, CYP1A2, CYP2C9, and CYP2D6. [21] 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), [46] erythromycin, itraconazole (Sporanox), ketoconazole (Nizoral), and mibefradil (Posicor). [47]
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
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. [59]
Additional drugs found to be affected by grapefruit juice include, but are not limited to
The grapefruit is a subtropical citrus tree known for its relatively large, sour to semi-sweet, somewhat bitter fruit. The interior flesh is segmented and varies in color from pale yellow to dark pink/red.
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In pharmaceutical sciences, drug interactions occur when a drug's mechanism of action is affected by the concomitant administration of substances such as foods, beverages, or other drugs. A popular example of drug–food interaction is the effect of grapefruit on the metabolism of drugs.
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Naringenin is a flavanone from the flavonoid group of polyphenols. It is commonly found in citrus fruits, especially as the predominant flavonone in grapefruit.
Naringin is a flavanone-7-O-glycoside between the flavanone naringenin and the disaccharide neohesperidose. The flavonoid naringin occurs naturally in citrus fruits, especially in grapefruit, where naringin is responsible for the fruit's bitter taste. In commercial grapefruit juice production, the enzyme naringinase can be used to remove the bitterness (debittering) created by naringin. In humans naringin is metabolized to the aglycone naringenin by naringinase present in the gut.
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Bergamottin (5-geranoxypsoralen) is a natural furanocoumarin found in the pulp of pomelos and grapefruits. It is also found in the peel and pulp of the bergamot orange, from which it was first isolated and from which its name is derived.
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6',7'-Dihydroxybergamottin is a natural furanocoumarin found in pomelos, grapefruits, and sour oranges, in both the peel and the pulp. Along with the chemically related compound bergamottin, it is believed to be responsible for a number of grapefruit–drug interactions, in which the consumption of citrus containing one or both of these compounds affects the metabolism of a variety of pharmaceutical drugs.
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