Some fruit and fruit juices can interact with many drugs, in many cases causing adverse effects. This effect was first discovered inadvertently, when drug-drug interactions tested using orange juice to hide the flavor of ethanol.
It is still best studied with grapefruit and grapefruit juice, but a similar effect has recently been seen with some (not all) other citrus fruits. One medical review advised patients to avoid all orange juice until further research explains the risks. Interacting chemicals are found in many plants, and so many other foods may be affected; effects have been observed with apple juice, but its clinical significance is unknown.
Normal amounts of food and beverages, such as one whole grapefruit or a small glass (200 ml (6.8 ppm) of grapefruit juice, can cause drug toxicity overdose.The fruit consumed three days before the drug can still be affected The relative risks of various citrus fruits have not studied systematically The affected medicines usually have additional labels that read "Do not take with grapefruit" in the container, and the interactions are described in packet inserts People are also advised to ask their doctor or pharmacist about drug interactions.
The effect is caused by furanocoumarins (and, to a lesser extent, flavonoids). These chemicals inhibit key drug metabolism enzymes, such as cytochrome P450 3A4 (CYP3A4). CYP3A4 is a metabolic enzyme for almost 50% of the drug, and is found in liver and small bowel epithelial cells. As a result, many drugs are affected. Inhibition of enzymes can have two different effects, depending on whether the drug is good
- metabolized by an enzyme into an inactive, or
- activated by enzyme to active metabolite.
If an active drug is metabolized by an inhibited enzyme, then the fruit will stop the metabolized drug, leaving an increased concentration of the drug in the body, which can cause adverse effects. Conversely, if the drug is a prodrug, it needs to be metabolized to be converted into an active drug. Compromising metabolism lowers the concentration of active drugs, reduces therapeutic effects, and risking treatment failure.
Low drug concentrations can also be caused when the fruit suppresses the absorption of the drug from the intestine.
Video Grapefruit-drug interactions
Histori
The effects of grapefruit juice in relation to drug absorption were initially discovered in 1989. The first report published on the 1991 Lancet drug interactions in Lancet was entitled "Orange Juice Interactions with Felodipine and Nifedipine," and was the first reported food drug. interaction clinically. However, the effect is only published well after being responsible for a number of bad interactions with drugs.
Maps Grapefruit-drug interactions
Active ingredients
Citrus fruits can contain a number of polyphenol compounds, including naroin flavonoids and furanocoumarin (such as bergamottin, dihydroxybergamottin, bergapten, and bergaptol). It is a natural chemical. They may be present in all forms of fruit, including fresh juices, frozen concentrates, and whole fruits.
Grapefruit, Seville oranges, bergamot, and possibly other oranges also contain naringin in large quantities. It takes up to 72 hours before the effects of naringin on CYP3A4 enzymes are seen. This problematic because 4 oz grapefruit portion contains enough naringin to inhibit the metabolism of CYP3A4 substrate. Naringin is a flavonoid that contributes to the bitter taste of grapefruit.
Furanocoumarins seem to have a stronger effect than naringin in some circumstances.
Mechanism
The organic compounds that are derived from furanocoumarin interfere with the liver and intestinal enzymes CYP3A4 and are believed to be responsible primarily for the effects of grapefruit on enzymes. Cytochrome isoforms affected by the grapefruit component also include CYP1A2, CYP2C9, and CYP2D6. Bioactive compounds in grapefruit juice may also interfere with MDR1 (multidrug resistance protein 1) and OATP (anion transport organic polypeptides), either increasing or decreasing the bioavailability of a number of drugs. Drugs that are metabolized by these enzymes may interact with the citrus chemicals.
When drugs are taken orally, they enter the intestinal lumen to be absorbed in the small intestine and sometimes, in the abdomen. In order for the drug to be absorbed, they must pass through the epithelial cells lining the lumen wall before they can enter the circulation of the liver portal to be systemically distributed in the blood circulation. Drugs are metabolized by the drug-specific metabolic enzymes in epithelial cells. The enzyme metabolization converts these drugs into metabolites. The main goal for drug metabolism is to detoxify, deactivate, dissolve and eliminate these drugs. As a result, the amount of drug in its original form that reaches the systemic circulation is reduced because of this first line metabolism.
Furanocoumarins (see section above) irreversibly inhibit the metabolic enzyme cytochrome P450 3A4 (CYP3A4). CYP3A4 is a metabolic enzyme for almost 50% of the drug, and is found in liver and small bowel epithelial cells. As a result, many drugs are affected by consumption of orange juice. When the metabolic enzyme is inhibited, less of the drug will be metabolized by it in epithelial cells. A decrease in drug metabolism means that more original forms of passing drugs do not change into the systemic blood circulation. High doses of unexpected drugs in the blood can cause fatal drug toxicity. CYP3A4 lies in the liver and enterocytes. Many oral agents undergo a first-pass (presystemic) metabolism by enzymes. Some organic compounds (see above section) found in oranges and especially in grapefruit juice exert inhibitory action on drug metabolism by enzymes.
This interaction is very dangerous when the drug has a low therapeutic index, so a small increase in blood concentration can be the difference between therapeutic effects and toxicity. Orange juice blocks enzymes only in the intestines if consumed in small amounts. Inhibition of intestinal enzymes will only affect the potential of oral medication.
When larger quantities are consumed they can also inhibit enzymes in the liver. Inhibition of liver enzymes may lead to an additional increase in potency and prolonged metabolic half-life (prolonged metabolic half-life for all drug delivery methods). The degree of effect varies widely between individuals and between juice samples, and therefore can not be accounted for a priori .
Another mechanism of interaction is possible through MDR1 (a multi-drug resistance protein 1) that is localized at the apical brush border of enterocytes. P-glycoprotein (Pgp) transports lipophilic molecules out of the enterocyte back into the intestinal lumen. Drugs that have lipophilic properties can be metabolized by CYP3A4 or dumped into the intestine by Pgp transporters. Both Pgp and CYP3A4 can act synergistically as a barrier to many orally administered drugs. Therefore, their inhibition (both or alone) can significantly increase the bioavailability of a drug.
Duration and time
Metabolic Interactions
Grapefruit drug interactions that affect pre-systemic metabolism (ie metabolism that occurs before the drug enters the blood) of drugs have different duration of action from interactions acting on other mechanisms, such as absorption, are discussed below.
This interaction is greatest when the juice is ingested with medication or up to 4 hours before medication.
The location of the inhibition occurs in the lining of the intestine, not in the liver. The effect persists because the inhibition of the enzyme mediated by grapefruit from drug metabolism enzymes, such as CYP3A4, can not be altered; that is, when grapefruit has "destroyed" enzymes, intestinal cells must produce more enzymes to restore their capacity to metabolize drugs used by enzymes to metabolize. It takes about 24 hours to regain 50% of the baseline cell enzyme activity and it takes 72 hours for the enzyme activity to return to the baseline completely. For this reason, simply separating the consumption of oranges and drugs taken daily does not avoid drug interactions.
Absorption interactions
For drugs that interact due to the inhibition of OATP (organic anion transport polypeptide), a relatively short time is required to avoid this interaction, and the 4 hour interval between grapefruit consumption and medication should be sufficient. For drugs that have recently been sold on the market, medicines have an information page (monograph) that provides information about potential interactions between drug and orange juice. As more and more drugs are known to interact with oranges, patients should consult a pharmacist or physician before eating oranges while taking their medication.
Affected fruits
Grapefruit is not the only citrus fruit that can interact with drugs; one medical review advises the patient to avoid all the oranges.
There are three ways to test whether fruit interacts with medicines:
- Test the fruit combination of drugs in humans
- Test the fruit chemically for the presence of interacting polyphenolic compounds
- Genetically test the fruit for the genes needed to make the interacting polifenol compound
The first approach involves the risk of trial volunteers. The first and second approach has another problem: the same fruit cultivar can be tested twice with different results. Depending on the growth and processing conditions, the concentrations of interacting polyphenolic compounds may vary dramatically. The third approach is hampered by a lack of knowledge about the genes concerned.
Genetics and orange interactions
Descendants of citrus cultivars that can not produce problematic polyphenolic compounds may also lack the gene to produce them. Many citrus cultivars are hybrids of a small number of ancestral species, which have now been fully sequenced genetically.
Many traditional citrus groups, such as real orange and lemon, seem to be the sport of buds, mutant descendants of a single hybrid ancestor. In theory, cultivars in a group of shoot sports will be all safe or all problematic. However, new citrus varieties that arrive on the market are increasingly likely to be sexually created hybrids, not sexually created sports.
Ancestors of hybrid cultivars may not be known. Even if it is known, it is impossible to ensure that cultivars will not interact with drugs based on taxonomy, since it is unknown what ancestors lacked the capacity to produce problematic polyphenol compounds. However, many known citrus cultivars seem to be closely related.
Ancestor Species
Pomelo (Asian fruit crossed with oranges to produce grapefruit) contains a large number of furanocoumarin derivatives. Relatives of grapefruit and other varieties of Balinese oranges have varying amounts of furanocoumarin.
The mandarin cultivar Dancy, which is not pure pure mandarin but has only a small contribution of grapefruit to their genome, has been tested once for furanocoumarins; nothing detected.
No citron or papeda has been tested.
Hybrid cultivars
Both sweet oranges and bitter oranges are mandarin-pomelo hybrids. Bitter oranges (such as Sevilla oranges often used in marmalade) can interfere with drugs including etoposide, chemotherapy drugs, 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 diverse.
Tests on some tangelos (hybrids of mandarin oranges/grapefruit and grapefruit or grapefruit) have not shown significant amounts of furanocoumarin.
The ordinary lemon is a product of citrus hybridization, and therefore has a grapefruit ancestor, and although Key limes are papeda/citron hybrids, the more common commercially Persian cones and similar varieties are Lime lime crucifixes with lemons, and hence also have grapefruit. offspring. This lime can also inhibit drug metabolism. Other less common orange species also known as lemons or limes are genetically distinct from more common varieties, with different proportions of pomelo ancestors.
Inaccurate labeling
Marketing classification is often incompatible with the taxonomy. The cultivars of "Ambersweet" are classified and sold as oranges, but not derived from the same ancestors as sweet oranges; has grapefruit, orange and mandarin ancestors. Fruits are often sold as mandarin, tangerine, or satsuma (which may be synonymous). Fruits sold under these names include many which, like Sunbursts and Murcotts, are hybrids with grapefruit ancestors. The variety of fruits called limes is amazing; some, like Spanish lime and Wild chalk, not even citrus fruits.
In some countries, citrus fruits should be labeled with the names of registered cultivars. Juice is often not so labeled. Some medical literature also mentions the name of the cultivars tested.
Other fruits and vegetables
The discovery that flavonoids are responsible for some interactions makes it plausible that other fruits and vegetables are affected.
Apple juice
Apple juice, especially commercially produced products, interferes with the actions of OATPs. This disorder can decrease the absorption of various commonly used drugs, including beta blockers such as atenolol, antibiotics such as ciprofloxacin, and antihistamines such as montelukast. Apple juice has been implicated in disrupting etoposide, chemotherapy drugs, and cyclosporine, taken by transplant patients to prevent rejection of their new organs.
Pomegranate juice
Pomegranate juice inhibits the action of metabolising drug enzymes CYP2C9 and CYP3A4. However, by 2014, the currently available literature does not appear to show clinically relevant effects of pomegranate juice on drugs metabolized by CYP2C9 and CYP3A4.
Affected drugs
Researchers have identified more than 85 drugs with grapefruit known to have adverse reactions. According to a review conducted by the Canadian Medical Association, there is an increasing number of potential drugs that can interact with orange juice, and from the amount of fruit that can interact with these drugs. From 2008 to 2012, the number of drugs known to potentially interact with grapefruit, with the risk of harmful or even harmful effects (gastrointestinal bleeding, nephrotoxicity), increased from 17 to 43.
Traits
The interaction between oranges and medications depends on each drug, and not its medication class. Interacting medicines usually share three common features: they are taken orally, usually only a small number enter the systemic blood circulation, and they are metabolized by CYP3A4. However, the effects on CYP3A4 in the liver can in principle lead to interactions with non-oral drugs, and non-CYP3A4-meditation effects also exist.
Cytochrome isoform is affected by grapefruit components including CYP3A4, CYP1A2, CYP2C9, and CYP2D6. Drugs that are metabolized by these enzymes may have interactions with the grapefruit component.
An easy way to know if a drug can be affected by orange juice is to examine whether other known CYP3A4 inhibitors have been contraindicated with the active drug from the drug in question. Examples of known CYP3A4 inhibitors include cisapride (Propulsid), erythromycin, itraconazole (Sporanox), ketoconazole (Nizoral), and mibefradil (Posicor).
The list of affected drugs is incomplete
With enzyme
Drugs that interact with the grapefruit compounds in CYP3A4 are included
- benzodiazepines: triazolam (Halcion), orally administered midazolam (Berp Versed), orally administered nitrazepam (Mogodon), diazepam (Valium), alprazolam (Xanax) and quazepam (Doral, Dormalin)
- amphetamines: dextroamphetamine and levoamphetamine (Dexedrine, Adderall)
- 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)
Drugs that interact with the grapefruit compounds in CYP1A2 are included
- caffeine
Drugs that interact with the grapefruit compounds in CYP2D6 are included
- dextroamphetamine (Dexedrine)
- levoamphetamine (Adderall)
- methamphetamine (Desoxyn)
Other stimulants that interact with CYP2D6 enzyme include
- methylphenidate (Ritalin, Concerta)
Research has been conducted on the interaction between amphetamines and CYP2D6 enzymes, and the researchers conclude that some parts of the substrate molecule contribute to enzyme binding.
Other interactions
Source of the article : Wikipedia
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