Some fruit juices and fruits can
interact with numerous drugs, in many cases causing
adverse effect
An adverse effect is an undesired harmful effect resulting from a medication or other intervention, such as surgery. An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. The term compli ...
s.
The effect is most studied with
grapefruit
The grapefruit (''Citrus'' × ''paradisi'') is a subtropical citrus tree known for its relatively large, sour to semi-sweet, somewhat bitter fruit. The flesh of the fruit is segmented and varies in color from pale yellow to dark red.
Grapefru ...
and
grapefruit juice,
[ but similar effects have been observed with certain other citrus fruits.]
One whole grapefruit, or a small glass () 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 advised to ask their physician
A physician, medical practitioner (British English), medical doctor, or simply doctor is a health professional who practices medicine, which is concerned with promoting, maintaining or restoring health through the Medical education, study, Med ...
or pharmacist
A pharmacist, also known as a chemist in English in the Commonwealth of Nations, Commonwealth English, is a healthcare professional who is knowledgeable about preparation, mechanism of action, clinical usage and legislation of medications in ...
about drug interactions. However, some experts believe that for the majority of patients, complete avoidance of grapefruit is unwarranted.
Although a prospective cohort study
A prospective cohort study is a longitudinal cohort study that follows over time a group of similar individuals ( cohorts) who differ with respect to certain factors under study to determine how these factors affect rates of a certain outcome. ...
of middle-aged women indicated that some flavonoid
Flavonoids (or bioflavonoids; from the Latin word ''flavus'', meaning yellow, their color in nature) are a class of polyphenolic secondary metabolites found in plants, and thus commonly consumed in the diets of humans.
Chemically, flavonoids ...
-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.
History
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 polyphenol
Polyphenols () are a large family of naturally occurring phenols. They are abundant in plants and structurally diverse. Polyphenols include phenolic acids, flavonoids, tannic acid, and ellagitannin, some of which have been used historically as ...
s, which may include furanocoumarins and naringin, such as bergamottin, dihydroxybergamottin, and bergapten
Bergapten (5-methoxypsoralen) is a naturally-occurring organic chemical compound produced by numerous plant species, especially from the carrot family Apiaceae and the citrus family Rutaceae. For example, bergapten has been extracted from 24 ...
. 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 enzyme
An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
s, 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. Organic derivatives of furanocoumarin interfere with liver
The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
and intestinal enzyme CYP3A4
Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...
and may be responsible for the effects of grapefruit on the enzyme. Cytochrome isoforms affected by grapefruit components include CYP1A2, CYP2C9, and CYP2D6
Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the ''CYP2D6'' gene. ''CYP2D6'' is primarily expressed in the liver. It is also highly expressed in areas of the central nervous system, including the substantia nigra.
CYP2 ...
, but CYP3A4 is the major CYP enzyme in the intestine.
Inhibition of enzymes can have two different effects:
# grapefruit juice-mediated inhibition of enzymes that metabolize the drug to an inactive metabolite
In biochemistry, a metabolite is an intermediate or end product of metabolism.
The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
leads to too high doses of the drug in the body
# grapefruit juice-mediated inhibition of membrane transport protein
A membrane transport protein is a membrane protein involved in the movement of ions, small molecules, and macromolecules, such as another protein, across a biological membrane. Transport proteins are integral membrane proteins, integral transmembr ...
s from the intestine to the blood, or inhibition of enzymes that activates a prodrug
A prodrug is a pharmacologically inactive medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be ...
to an active metabolite leads to insufficient doses of the drug in the body resulting in loss of theurapeutic effect
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. 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. 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
The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascular system. ...
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 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
Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...
, 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
''Citrus'' is a genus of flowering plant, flowering trees and shrubs in the family Rutaceae. Plants in the genus produce citrus fruits, including important crops such as Orange (fruit), oranges, Mandarin orange, mandarins, lemons, grapefruits, ...
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
A cultivar is a kind of Horticulture, cultivated plant that people have selected for desired phenotypic trait, traits and which retains those traits when Plant propagation, propagated. Methods used to propagate cultivars include division, root a ...
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
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 pomelo ( ; or pummelo, ''Citrus maxima''), also known as a shaddock, is the largest citrus fruit. It is an ancestor of several cultivated citrus species, including the bitter orange and the grapefruit. It is a natural, non-hybrid citrus fr ...
(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.
Hybrid cultivars
Both sweet oranges and bitter oranges are mandarin-pomelo
The pomelo ( ; or pummelo, ''Citrus maxima''), also known as a shaddock, is the largest citrus fruit. It is an ancestor of several cultivated citrus species, including the bitter orange and the grapefruit. It is a natural, non-hybrid citrus fr ...
hybrids.[ Bitter oranges (such as the Seville oranges often used in ]marmalade
Marmalade (from the Portuguese ''marmelada'') is a fruit preserves, fruit preserve made from the juice and peel of citrus fruits boiled with sugar and water. The well-known version is made from bitter orange. It also has been made from lemons ...
) can interfere with drugs including etoposide
Etoposide, sold under the brand name Vepesid among others, is a chemotherapy medication used for the treatments of a number of types of cancer including testicular cancer, lung cancer, lymphoma, leukemia, neuroblastoma, and ovarian cancer. It is ...
, a chemotherapy drug, some beta blocker
Beta blockers, also spelled β-blockers, are a class of medications that are predominantly used to manage abnormal heart rhythms ( arrhythmia), and to protect the heart from a second heart attack after a first heart attack ( secondary prevention ...
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 marketed 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
The tangerine is a type of citrus fruit that is orange in colour, that is considered either a variety of the mandarin orange (''Citrus reticulata''), or a closely related species, under the name ''Citrus tangerina'', or yet as a hybrid (''Citr ...
, or satsuma (which may be synonyms). Fruit sold under these names include many that are, like Sunbursts and Murcotts, 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
Atenolol is a beta blocker medication primarily used to treat high blood pressure and angina, heart-associated chest pain. Although used to treat high blood pressure, it does not seem to improve mortality rate, mortality in those with the condi ...
, antibiotics
An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting pathogenic bacteria, bacterial infections, and antibiotic medications are widely used in the therapy ...
like ciprofloxacin
Ciprofloxacin is a fluoroquinolone antibiotic used to treat a number of bacterial infections. This includes bone and joint infections, intra-abdominal infections, certain types of infectious diarrhea, respiratory tract infections, skin ...
, and antihistamines
Antihistamines are drugs which treat allergic rhinitis, common cold, influenza, and other allergies. Typically, people take antihistamines as an inexpensive, generic (not patented) drug that can be bought without a prescription and provides r ...
like montelukast
Montelukast, sold under the brand name Singulair among others, is a medication used in the maintenance treatment of asthma. It is generally less preferred for this use than inhaled corticosteroids. It is not useful for acute asthma attacks. ...
.
Pomegranate juice
Pomegranate juice inhibits the action of the drug metabolizing enzymes CYP2C9 and CYP3A4
Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...
. , 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, 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
Gastrointestinal bleeding (GI bleed), also called gastrointestinal hemorrhage (GIB), is all forms of bleeding in the gastrointestinal tract, from the mouth to the rectum. When there is significant blood loss over a short time, symptoms may includ ...
, nephrotoxicity
Nephrotoxicity is toxicity in the kidneys. It is a poisonous effect of some substances, both toxic chemicals and medications, on kidney function. There are various forms, and some drugs may affect kidney function in more than one way. Nephrotoxin ...
), 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-CYP3A4-mediated effects.
Cytochrome isoforms affected by grapefruit components include CYP3A4
Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...
, CYP1A2, CYP2C9, and CYP2D6
Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the ''CYP2D6'' gene. ''CYP2D6'' is primarily expressed in the liver. It is also highly expressed in areas of the central nervous system, including the substantia nigra.
CYP2 ...
. 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
In medicine, a contraindication is a condition (a situation or factor) that serves as a reason not to take a certain medical treatment due to the harm that it would cause the patient. Contraindication is the opposite of indication, which is a rea ...
with the active drug of the medication in question. Examples of such known CYP3A4 inhibitors include cisapride (Propulsid), erythromycin
Erythromycin is an antibiotic used for the treatment of a number of bacterial infections. This includes respiratory tract infections, skin infections, chlamydia infections, pelvic inflammatory disease, and syphilis. It may also be used ...
, itraconazole
Itraconazole, sometimes abbreviated ITZ, is an antifungal medication used to treat a number of fungal infections. This includes aspergillosis, blastomycosis, coccidioidomycosis, histoplasmosis, and paracoccidioidomycosis. It may be given ...
(Sporanox), ketoconazole
Ketoconazole, sold under the brand name Nizoral, among others, is an antiandrogen, antifungal drug, antifungal, and antiglucocorticoid medication used to treat a number of fungal infections. Applied to the skin it is used for fungal skin inf ...
(Nizoral), and mibefradil (Posicor).
Incomplete list of affected drugs
By enzyme
Drugs that interact with grapefruit compounds at CYP3A4 include:
* benzodiazepine
Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant, depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed t ...
s: triazolam
Triazolam, sold under the brand name Halcion among others, is a central nervous system (CNS) depressant tranquilizer of the triazolobenzodiazepine (TBZD) class, which are benzodiazepine (BZD) derivatives. It possesses pharmacological properti ...
(Halcion), orally administered midazolam
Midazolam, sold under the brand name Versed among others, is a benzodiazepine medication used for anesthesia, premedication before surgical anesthesia, and procedural sedation, and to treat psychomotor agitation, severe agitation. It induces ...
(Versed), orally administered nitrazepam (Mogodon), diazepam
Diazepam, sold under the brand name Valium among others, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is used to treat a range of conditions, including anxiety disorder, anxiety, seizures, alcohol withdrawal syndr ...
(Valium), clonazepam (Klonopin), alprazolam
Alprazolam, sold under the brand name Xanax among others, is a fast-acting, potent tranquilizer of moderate duration within the triazolobenzodiazepine group of chemicals called benzodiazepines. Alprazolam is most commonly prescribed in the ...
(Xanax) and quazepam (Doral, Dormalin)
* ritonavir (Norvir): Inhibition of CYP3A4 prevents the metabolism of protease inhibitors such as ritonavir.
* sertraline
Sertraline, sold under the brand name Zoloft among others, is an Antidepressant, antidepressant medication of the selective serotonin reuptake inhibitor (SSRI) class used to treat major depressive disorder, generalized anxiety disorder, socia ...
(Zoloft and Lustral)
* verapamil (Covera-HS, Calan, Verelan, and Isoptin)
Drugs that interact with grapefruit compounds at CYP1A2 include:
* caffeine
Caffeine is a central nervous system (CNS) stimulant of the methylxanthine chemical classification, class and is the most commonly consumed Psychoactive drug, psychoactive substance globally. It is mainly used for its eugeroic (wakefulness pr ...
Drugs that interact with grapefruit compounds at CYP2D6 include:
* dextroamphetamine
Dextroamphetamine (international nonproprietary name, INN: dexamfetamine) is a potent central nervous system (CNS) stimulant and enantiomer of amphetamine that is used in the treatment of attention deficit hyperactivity disorder (ADHD) and narc ...
(Dexedrine)
* dextroamphetamine (75%)/ levoamphetamine
Levoamphetamine is a stimulant medication which is used in the treatment of certain medical conditions. It was previously marketed by itself under the brand name Cydril, but is now available only in combination drug, combination with dextroam ...
(25%) (Adderall)
* dextromethamphetamine (Desoxyn)
Research has been done on the interaction between amphetamines
Substituted amphetamines, or simply amphetamines, are a chemical class, class of compounds based upon the amphetamine structure; it includes all derivative (chemistry), derivative compounds which are formed by replacing, or substitution reacti ...
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 statin
Statins (or HMG-CoA reductase inhibitors) are a class of medications that lower cholesterol. They are prescribed typically to people who are at high risk of cardiovascular disease.
Low-density lipoprotein (LDL) carriers of cholesterol play ...
s, including atorvastatin
Atorvastatin, sold under the brand name Lipitor among others, is a statin medication used to prevent cardiovascular disease in those at high risk and to treat abnormal lipid levels. For the prevention of cardiovascular disease, statins are a ...
(Lipitor), lovastatin (Mevacor), and simvastatin
Simvastatin, sold under the brand name Zocor among others, is a statin, a type of lipid-lowering medication. It is used along with exercise, diet, and weight loss to decrease hyperlipidemia, elevated lipid levels. It is also used to decrease t ...
(Zocor, Simlup, Simcor, Simvacor)
** In contrast, pravastatin (Pravachol), fluvastatin (Lescol), and rosuvastatin (Crestor) are unaffected by grapefruit.
* Anti-arrhythmics including amiodarone
Amiodarone is an antiarrhythmic medication used to treat and prevent a number of types of cardiac dysrhythmias. This includes ventricular tachycardia, ventricular fibrillation, and wide complex tachycardia, atrial fibrillation, and paroxys ...
(Cordarone), dronedarone (Multaq), quinidine
Quinidine is a class I antiarrhythmic agent, class IA antiarrhythmic agent used to treat heart rhythm disturbances. It is a diastereomer of Antimalarial medication, antimalarial agent quinine, originally derived from the bark of the cinchona tre ...
(Quinidex, Cardioquin, Quinora), disopyramide (Norpace), propafenone (Rythmol) and carvedilol (Coreg)
* Amlodipine
Amlodipine, sold under the brand name Norvasc among others, is a calcium channel blocker medication used to treat hypertension, high blood pressure, coronary artery disease (CAD) and variant angina (also called Prinzmetal angina or coronary ar ...
: 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)
* Erectile dysfunction
Erectile dysfunction (ED), also referred to as impotence, is a form of sexual dysfunction in males characterized by the persistent or recurring inability to achieve or maintain a Human penis, penile erection with sufficient rigidity and durat ...
drugs sildenafil
Sildenafil, sold under the brand name Viagra among others, is a medication used to treat erectile dysfunction and pulmonary hypertension, pulmonary arterial hypertension. It is also sometimes used off-label for the treatment of certain sym ...
(Viagra), tadalafil (Cialis) and vardenafil (Levitra)
* 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.
* Anthelmintic
Anthelmintics or antihelminthics are a group of antiparasitic drugs that expel parasitic worms (helminths) and other internal parasites from the body by either stunning or killing them without causing significant damage to the host. They may also ...
s: Used for treating certain parasitic infections; includes praziquantel
* Buprenorphine: Metabolized into norbuprenorphine by CYP3A4
* Buspirone
Buspirone, sold under the brand name Buspar among others, is an anxiolytic, a medication primarily used to treat anxiety disorders, particularly generalized anxiety disorder (GAD). It is a serotonin 5-HT1A receptor, 5-HT1A receptor partial ag ...
(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
Morphine, formerly also called morphia, is an opiate that is found naturally in opium, a dark brown resin produced by drying the latex of opium poppies (''Papaver somniferum''). It is mainly used as an analgesic (pain medication). There are ...
entirely by CYP2D6.
* Ciclosporin
Ciclosporin, also spelled cyclosporine and cyclosporin, is a calcineurin inhibitor, used as an immunosuppressant medication. It is taken Oral administration, orally or intravenously for rheumatoid arthritis, psoriasis, Crohn's disease, nephr ...
(cyclosporine, Neoral): Blood levels of ciclosporin are increased if taken with grapefruit juice, orange juice, or apple juice.[ A plausible mechanism involves the combined inhibition of enteric CYP3A4 and MDR1, which potentially leads to serious adverse events (e.g., nephrotoxicity). Blood levels of ]tacrolimus
Tacrolimus, sold under the brand name Prograf among others, is an immunosuppressive drug. After Allotransplantation, allogenic organ transplant, the risk of organ Transplant rejection, rejection is moderate. To lower the risk of organ rejectio ...
(Prograf) can also be equally affected for the same reason as ciclosporin, as both drugs are calcineurin inhibitors.
* Dihydropyridines including felodipine (Plendil), nicardipine (Cardene), nifedipine, nisoldipine (Sular) and nitrendipine (Bayotensin)
* Erlotinib (Tarceva)
* 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.[
* Fexofenadine (Allegra) concentrations are decreased rather than increased as is the case with most grapefruit–drug interactions.
* 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)
* Methadone: Inhibits the metabolism of methadone and raises serum levels.
* 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)
* Sirolimus (Rapamycin, Rapamune)
* 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.
* Warfarin (coumadin)[Jellin J.M., et al. Pharmacist's Letter/Prescriber's Letter of Natural Medicines Comprehensive Database. 7th ed. Stockton, CA: Therapeutic Research Faculty. 2005. 626-629]
* Zolpidem (Ambien): Little or no interaction with grapefruit juice
References
{{DEFAULTSORT:Grapefruit-drug interactions
Pharmacokinetics
Medical lists, Drugs affected by grapefruit
Grapefruit
Furanocoumarins