List of drugs affected by grapefruit
Encyclopedia
Grapefruit
and grapefruit juice have the potential to interact
with numerous drugs
. A number of organic compounds, identified as furanocoumarin
derivatives, interfere with the hepatic
and intestinal
enzyme
cytochrome P450 isoform CYP3A4
and are therefore primarily responsible for the interaction. However, bioactive compounds in grapefruit juice may also interfere with P-glycoprotein
and organic anion transporting polypeptide
s (OATPs) either increasing or decreasing bioavailability of a number of drugs. Pomelo
(the Asian fruit which was crossed with an orange to produce grapefruit) also contains high amounts of furanocoumarin
derivatives.
ingestion and medication with the dihydropyridine calcium channel blocker
- felodipine
. Grapefruit
juice was used as a flavouring additive to mask the taste of alcohol during the test. The results of study showed several-fold increase of felodipine concentrations compared to results obtained in other investigations of the drug. Additionally, there were lower blood pressure readings and more adverse effects compared to the group of subjects on felodipine alone. Further investigations revealed that grapefruit juice strikingly elevated
felodipine bioavailability and could influence its other pharmacokinetic and pharmacodynamic properties.
In October 2011, researchers at the university of Florida announced that a grapefruit
-pummelo hybrid with low furanocoumarin
content is under development. This hybrid fruit is presumed to have a low potential for drug interaction
s, unlike traditional grapefruit varietals.
inhibition with grapefruit compounds:
Additional drugs found to be affected by grapefruit juice include, but are not limited to:
s. Many oral drugs undergo first-pass (presystemic) metabolism by the enzyme. Several organic compounds found in grapefruit and specifically in grapefruit juice exert inhibitory action on drug metabolism by the enzyme. It has been established that a group of compounds called furanocoumarins are responsible for this interaction and not flavonoids as was previously reported.
The list of active furanocoumarins found in grapefruit juice includes: bergamottin
, bergapten
, bergaptol and 6',7'-dihydroxybergamottin.
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 success and toxicity. Grapefruit juice only inhibits the enzyme within the intestines, not in the liver
or elsewhere in the body, and does not impact injected drugs. The degree of the effect varies widely between individuals and between samples of juice, therefore it cannot be accounted for a priori.
Another mechanism of interaction is possibly through the P-glycoprotein
(Pgp) that is localized in the apical brush border
of the enterocytes. Pgp transports lipophilic
molecules out of the enterocyte back into the intestinal lumen. Drugs that possess lipophilic properties are either metabolised by CYP3A4 or removed into the intestine by the Pgp transporter. Both the Pgp and CYP3A4 may act synergistically as a barrier to many orally administered drugs. Therefore their inhibition (both or alone) can markedly increase the bioavailability of a drug.
The interaction caused by grapefruit compounds lasts for up to 24 hours and its effect is the greatest when the juice is ingested with the drug or up to 4 hours before the drug.
The flavonoid
existing in highest concentration in grapefruit juice is naringin
, which in humans is metabolised to naringenin
. There are also other flavonoids in grapefruit juice, in lower concentrations. Orange juice
does not contain naringin
in as high a concentration, instead containing hesperetin
. It is sometimes recommended as a substitute. Juice of lime
s and Seville oranges can also inhibit drug metabolism, however, as can apple
juice with some drugs.
Grapefruit
The grapefruit , is a subtropical citrus tree known for its sour fruit, an 18th-century hybrid first bred in Barbados. When found, it was named the "forbidden fruit"; it has also been misidentified with the pomelo or shaddock , one of the parents of this hybrid, the other being sweet orange The...
and grapefruit juice have the potential to interact
Drug interaction
A drug interaction is a situation in which a substance affects the activity of a drug, i.e. the effects are increased or decreased, or they produce a new effect that neither produces on its own. Typically, interaction between drugs come to mind...
with numerous drugs
DRUGS
Destroy Rebuild Until God Shows are an American post-hardcore band formed in 2010. They released their debut self-titled album on February 22, 2011.- Formation :...
. A number of organic compounds, identified as furanocoumarin
Furanocoumarin
Furanocoumarins, or furocoumarins, are a class of organic chemical compounds produced by a variety of plants. They are biosynthesized partly through the phenylpropanoid pathway and the mevalonate pathway, which is biosynthesized by a coupling of dimethylallyl pyrophosphate and 7-hydroxycoumarin...
derivatives, interfere with the hepatic
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
and intestinal
Intestine
In human anatomy, the intestine is the segment of the alimentary canal extending from the pyloric sphincter of the stomach to the anus and, in humans and other mammals, consists of two segments, the small intestine and the large intestine...
enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
cytochrome P450 isoform CYP3A4
CYP3A4
Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
and are therefore primarily responsible for the interaction. However, bioactive compounds in grapefruit juice may also interfere with P-glycoprotein
P-glycoprotein
P-glycoprotein 1 also known as multidrug resistance protein 1 or ATP-binding cassette sub-family B member 1 or cluster of differentiation 243 is a glycoprotein that in humans is encoded by the ABCB1 gene...
and organic anion transporting polypeptide
Organic anion transporting polypeptide
An organic anion-transporting polypeptide is a membrane transport protein that mediates the transport of organic anions across the cell membrane...
s (OATPs) either increasing or decreasing bioavailability of a number of drugs. Pomelo
Pomelo
The pomelo is a citrus fruit native to Southeast Asia. It is usually pale green to yellow when ripe, with sweet white flesh and very thick albedo . It is the largest citrus fruit, 15–25 cm in diameter, and usually weighing 1–2 kg...
(the Asian fruit which was crossed with an orange to produce grapefruit) also contains high amounts of furanocoumarin
Furanocoumarin
Furanocoumarins, or furocoumarins, are a class of organic chemical compounds produced by a variety of plants. They are biosynthesized partly through the phenylpropanoid pathway and the mevalonate pathway, which is biosynthesized by a coupling of dimethylallyl pyrophosphate and 7-hydroxycoumarin...
derivatives.
History
In 1989 a pharmacological study evaluated the possibility of an interaction between ethanolEthanol
Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...
ingestion and medication with the dihydropyridine calcium channel blocker
Calcium channel blocker
A calcium channel blocker is a chemical that disrupts the movement of calcium through calcium channels.CCB drugs devised to target neurons are used as antiepileptics. However, the most widespread clinical usage of calcium channel blockers is to decrease blood pressure in patients with...
- felodipine
Felodipine
Felodipine is a calcium channel blocker , a drug used to control hypertension . It is marketed under the brand name Plendil by AstraZeneca and Renedil by Sanofi-Aventis...
. Grapefruit
Grapefruit
The grapefruit , is a subtropical citrus tree known for its sour fruit, an 18th-century hybrid first bred in Barbados. When found, it was named the "forbidden fruit"; it has also been misidentified with the pomelo or shaddock , one of the parents of this hybrid, the other being sweet orange The...
juice was used as a flavouring additive to mask the taste of alcohol during the test. The results of study showed several-fold increase of felodipine concentrations compared to results obtained in other investigations of the drug. Additionally, there were lower blood pressure readings and more adverse effects compared to the group of subjects on felodipine alone. Further investigations revealed that grapefruit juice strikingly elevated
felodipine bioavailability and could influence its other pharmacokinetic and pharmacodynamic properties.
In October 2011, researchers at the university of Florida announced that a grapefruit
Grapefruit
The grapefruit , is a subtropical citrus tree known for its sour fruit, an 18th-century hybrid first bred in Barbados. When found, it was named the "forbidden fruit"; it has also been misidentified with the pomelo or shaddock , one of the parents of this hybrid, the other being sweet orange The...
-pummelo hybrid with low furanocoumarin
Furanocoumarin
Furanocoumarins, or furocoumarins, are a class of organic chemical compounds produced by a variety of plants. They are biosynthesized partly through the phenylpropanoid pathway and the mevalonate pathway, which is biosynthesized by a coupling of dimethylallyl pyrophosphate and 7-hydroxycoumarin...
content is under development. This hybrid fruit is presumed to have a low potential for drug interaction
Drug interaction
A drug interaction is a situation in which a substance affects the activity of a drug, i.e. the effects are increased or decreased, or they produce a new effect that neither produces on its own. Typically, interaction between drugs come to mind...
s, unlike traditional grapefruit varietals.
Affected drugs
The following drugs are affected by CYP3A4CYP3A4
Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
inhibition with grapefruit compounds:
- The benzodiazepineBenzodiazepineA benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
s triazolamTriazolamTriazolam is a benzodiazepine drug. It possesses pharmacological properties similar to that of other benzodiazepines, but it is generally only used as a sedative to treat severe insomnia...
(Halcion), orally administered midazolamMidazolamMidazolam is a short-acting drug in the benzodiazepine class developed by Hoffmann-La Roche in the 1970s. The drug is used for treatment of acute seizures, moderate to severe insomnia, and for inducing sedation and amnesia before medical procedures. It possesses profoundly potent anxiolytic,...
(Versed), orally administered diazepamDiazepamDiazepam , first marketed as Valium by Hoffmann-La Roche is a benzodiazepine drug. Diazepam is also marketed in Australia as Antenex. It is commonly used for treating anxiety, insomnia, seizures including status epilepticus, muscle spasms , restless legs syndrome, alcohol withdrawal,...
(Valium), alprazolamAlprazolamAlprazolam is a short-acting anxiolytic of the benzodiazepine class of psychoactive drugs. Alprazolam, like other benzodiazepines, binds to specific sites on the GABAA gamma-amino-butyric acid receptor...
(Xanax) and quazepamQuazepamQuazepam is a benzodiazepine derivative drug developed by the Schering Corporation in the 1970s. Quazepam is indicated for the treatment of insomnia including sleep induction and sleep maintenance... - ritonavirRitonavirRitonavir, with trade name Norvir , is an antiretroviral drug from the protease inhibitor class used to treat HIV infection and AIDS....
(Norvir) inhibits CYP3A4 preventing the metabolism of protease inhibitors - sertralineSertralineSertraline hydrochloride is an antidepressant of the selective serotonin reuptake inhibitor class. It was introduced to the market by Pfizer in 1991. Sertraline is primarily used to treat major depression in adult outpatients as well as obsessive–compulsive, panic, and social anxiety disorders in...
(Zoloft and Lustral)
Additional drugs found to be affected by grapefruit juice include, but are not limited to:
- StatinStatinStatins are a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver. Increased cholesterol levels have been associated with cardiovascular diseases, and statins are therefore used in the...
s such as atorvastatinAtorvastatinAtorvastatin , sold by Pfizer under the trade name Lipitor, is a member of the drug class known as statins, used for lowering blood cholesterol. It also stabilizes plaque and prevents strokes through anti-inflammatory and other mechanisms...
(Lipitor), lovastatinLovastatinLovastatin is a member of the drug class of statins, used for lowering cholesterol in those with hypercholesterolemia and so preventing cardiovascular disease...
(Mevacor), and simvastatinSimvastatinSimvastatin is a hypolipidemic drug used to control elevated cholesterol, or hypercholesterolemia. Simvastatin is a member of the statin class of pharmaceuticals, is a synthetic derivate of a fermentation product of Aspergillus terreus.-Medical uses:The primary uses of simvastatin is for the...
(Zocor, Simlup, Simcard, Simvacor) with the exception of PravastatinPravastatinPravastatin is a member of the drug class of statins, used for lowering cholesterol and preventing cardiovascular disease. Initially known as CS-514, it was originally identified in a bacterium called Nocardia autotrophica by researchers of the Sankyo Pharma Inc....
(Pravachol), fluvastatinFluvastatinFluvastatin is a member of the drug class of statins, used to treat hypercholesterolemia and to prevent cardiovascular disease....
(Lescol) and rosuvastatinRosuvastatinRosuvastatin is a member of the drug class of statins, used to treat high cholesterol and related conditions, and to prevent cardiovascular disease. It was developed by Shionogi.-Medical uses:The primary uses of rosuvastatin is for the treatment of dyslipidemia...
(Crestor) which are unaffected by grapefruit. - DihydropyridinesDihydropyridinesDihydropyridine is a molecule based upon pyridine, and the parent of a class of molecules that have been semi-saturated with two substituents replacing one double bond. They are particularly well known in pharmacology as L-type calcium channel blockers....
including felodipineFelodipineFelodipine is a calcium channel blocker , a drug used to control hypertension . It is marketed under the brand name Plendil by AstraZeneca and Renedil by Sanofi-Aventis...
(Plendil), nicardipineNicardipineNicardipine hydrochloride is a medication used to treat high blood pressure and angina. It belongs to the class of calcium channel blockers....
(Cardene), nifedipineNifedipineNifedipine is a dihydropyridine calcium channel blocker...
, nisoldipineNisoldipineNisoldipine is a calcium channel blocker of the dihydropyridine class. It sold in the United States under the proprietary name Sular. Nisoldipine has tropism for cardiac blood vessels....
(Sular), nitrendipineNitrendipineNitrendipine is a dihydropyridine calcium channel blocker. It is used in the treatment of primary hypertension to decrease blood pressure....
(Bayotensin) - losartanLosartanLosartan is an angiotensin II receptor antagonist drug used mainly to treat high blood pressure . Losartan was the first angiotensin II receptor antagonist to be marketed. Losartan potassium is marketed by Merck & Co. Inc. under the trade name Cozaar...
(Cozaar) - The cough suppressant dextromethorphanDextromethorphanDextromethorphan is an antitussive drug. It is one of the active ingredients in many over-the-counter cold and cough medicines, such as Robitussin, NyQuil, Dimetapp, Vicks, Coricidin, Delsym, and others, including generic labels. Dextromethorphan has also found other uses in medicine, ranging...
- modafinilModafinilModafinil is an analeptic drug manufactured by Cephalon, and is approved by the U.S. Food and Drug Administration for the treatment of narcolepsy, shift work sleep disorder, and excessive daytime sleepiness associated with obstructive sleep apnea...
(Provigil, Alertec, Modavigil, Modalert, Modiodal, Modafinilo, Carim, Vigia) - repaglinideRepaglinideRepaglinide is for the treatment of type II diabetes. It is supplied by Novo Nordisk...
(Prandin) - verapamilVerapamilVerapamil is an L-type calcium channel blocker of the phenylalkylamine class. It has been used in the treatment of hypertension, angina pectoris, cardiac arrhythmia, and most recently, cluster headaches. It is also an effective preventive medication for migraine...
(Calan SR, Covera HS, Isoptin SR, Verelan) - buspironeBuspironeBuspirone is an anxiolytic psychoactive drug of the azapirone chemical class, and is primarily used to treat generalized anxiety disorder Bristol-Myers Squibb gained FDA approval of buspirone in 1986 for treatment of GAD...
(Buspar) - levothyroxineLevothyroxineLevothyroxine, also L-thyroxine, synthetic T4, or 3,5,3',5'-tetraiodo-L-thyronine, is a synthetic form of thyroxine , used as a hormone replacement for patients with thyroid problems. The natural hormone is chemically in the chiral L-form, as is the pharmaceutical agent...
(Eltroxin, Levoxyl, Synthroid) - Antiarrhythmics including amiodaroneAmiodaroneAmiodarone is an antiarrhythmic agent used for various types of tachyarrhythmias , both ventricular and supraventricular arrhythmias. Discovered in 1961, it was not approved for use in the United States until 1985...
(Cordarone), dronedaroneDronedaroneDronedarone is a drug by Sanofi-Aventis, mainly for the indication of cardiac arrhythmias. It was approved by the FDA on July 2, 2009. It is now available as 400 mg tablets in 20, 60 and 100 count packages...
(Multaq), quinidineQuinidineQuinidine is a pharmaceutical agent that acts as a class I antiarrhythmic agent in the heart. It is a stereoisomer of quinine, originally derived from the bark of the cinchona tree.-Mechanism:...
(Quinidex, Cardioquin, Quinora), disopyramideDisopyramideDisopyramide is an antiarrhythmic medication. It is a Class Ia antiarrhythmic used in the treatment of ventricular tachycardias...
(Norpace), propafenonePropafenonePropafenone is a class Ic anti-arrhythmic medication, which treats illnesses associated with rapid heart beats such as atrial and ventricular arrhythmias.-Mechanism of action:...
(Rhythmol), and carvedilolCarvedilolCarvedilol is a non-selective beta blocker/alpha-1 blocker indicated in the treatment of mild to moderate congestive heart failure . It is marketed under various trade names including Carvil , Coreg , Dilatrend , Eucardic , and Carloc as a generic drug ., and as a...
(Coreg) - Antihistamines astemizoleAstemizoleAstemizole was a second generation antihistamine drug which has a long duration of action. Astemizole was discovered by Janssen Pharmaceutica in 1977...
(Hismanal) and terfenadineTerfenadineTerfenadine is an antihistamine formerly used for the treatment of allergic conditions. It was brought to market by Hoechst Marion Roussel and marketed under various brand names including Seldane in the United States, Triludan in the United Kingdom, and Teldane in Australia...
(Seldane) - now removed from the US and Canadian markets - cisaprideCisaprideCisapride is a gastroprokinetic agent, a drug which increases motility in the upper gastrointestinal tract. It acts directly as a serotonin 5-HT4 receptor agonist and indirectly as a parasympathomimetic. Stimulation of the serotonin receptors increases acetylcholine release in the enteric nervous...
(Prepuslid, Propulsid) (which treats GERD) - now removed from the US and Canadian markets - Erectile dysfunction drugs sildenafilSildenafilSildenafil citrate, sold as Viagra, Revatio and under various other trade names, is a drug used to treat erectile dysfunction and pulmonary arterial hypertension . It was originally developed by British scientists and then brought to market by the US-based pharmaceutical company Pfizer...
(Viagra), tadalafilTadalafilTadalafil is a PDE5 inhibitor, currently marketed in pill form for treating erectile dysfunction under the name Cialis; and under the name Adcirca for the treatment of pulmonary arterial hypertension...
(Cialis), and vardenafilVardenafilVardenafil is a PDE5 inhibitor used for treating erectile dysfunction that is sold under the trade names Levitra and Staxyn.-History:...
(Levitra) - The anti-migraine drugs ergotamine (Cafergot, Ergomar), amitryptiline (Elavil, Endep, Vanatrip) and nimodipineNimodipineNimodipine is a dihydropyridine calcium channel blocker originally developed for the treatment of high blood pressure...
(Nimotop) - FluvoxamineFluvoxamineFluvoxamine is an antidepressant which functions as a selective serotonin reuptake inhibitor . Fluvoxamine was first approved by the U.S. Food and Drug Administration in 1993 for the treatment of obsessive compulsive disorder . Fluvoxamine CR is approved to treat social anxiety disorder...
(Luvox, Faverin, Fevarin and Dumyrox) - CodeineCodeineCodeine or 3-methylmorphine is an opiate used for its analgesic, antitussive, and antidiarrheal properties...
and TramadolTramadolTramadol hydrochloride is a centrally acting synthetic opioid analgesic used in treating moderate pain. The drug has a wide range of applications, including treatment for restless legs syndrome and fibromyalgia...
. It reduces the amount of codeine converted by CYP3A4 into norcodeineNorcodeineNorcodeine is an opiate analogue that is the N-demethylated derivative of codeine.Norcodeine has relatively little opioid activity in its own right, but is formed as a metabolite of codeine following ingestion....
thus increasing the amount metabolized into morphine. Morphine itself, however, is not affected by grapefruit juice, as it is not metabolized by the cytochrome P450 system. - Cyclosporine (Neoral). Blood levels of cyclosporine are increased if taken with grapefruit juice. A plausible mechanism involves the combined inhibition of enteric CYP3A4 and P-glycoprotein, which potentially leads to serious adverse events (e.g., nephrotoxicity).Blood levels of tacrolimusTacrolimusTacrolimus is an immunosuppressive drug that is mainly used after allogeneic organ transplant to reduce the activity of the patient's immune system and so lower the risk of organ rejection...
(Prograf) can also be equally affected for the same reason as with cyclosporine. [both drugs are calcineurin inhibitors] - omeprazoleOmeprazoleOmeprazole is a proton pump inhibitor used in the treatment of dyspepsia, peptic ulcer disease , gastroesophageal reflux disease , laryngopharyngeal reflux and Zollinger–Ellison syndrome...
(Losec, Prilosec) - zolpidemZolpidemZolpidem is a prescription medication used for the short-term treatment of insomnia, as well as some brain disorders. It is a short-acting nonbenzodiazepine hypnotic of the imidazopyridine class that potentiates gamma-aminobutyric acid , an inhibitory neurotransmitter, by binding to GABAA...
(Ambien) Little or no interaction with grapefruit juice. - oxycodoneOxycodoneOxycodone is an opioid analgesic medication synthesized from opium-derived thebaine. It was developed in 1916 in Germany, as one of several new semi-synthetic opioids in an attempt to improve on the existing opioids: morphine, diacetylmorphine , and codeine.Oxycodone oral medications are generally...
(Oxycodone is metabolized by the cytochrome P450 system, specifically CYP3A4, of which the bergamottinBergamottinBergamottin is a natural furanocoumarin found principally in grapefruit juice. It is also found in the oil of bergamot, from which it was first isolated and from which its name is derived. To a lesser extent, bergamottin is also present in the essential oils of other citrus fruits...
flavonoid is a strong inhibitor) - hydrocodoneHydrocodoneHydrocodone or dihydrocodeinone is a semi-synthetic opioid derived from either of two naturally occurring opiates: codeine and thebaine. It is an orally active narcotic analgesic and antitussive...
(The hepatic cytochrome P450 enzyme CYP2D6 converts it into hydromorphone, a more potent opioid.) - dihydrocodeineDihydrocodeineDihydrocodeine, also called DHC, Drocode, Paracodeine and Parzone and known by the brand names of Synalgos DC, Panlor DC, Panlor SS, Contugesic, New Bron Solution-ACE, Huscode, Drocode, Paracodin, Codidol, Didor Continus, Dicogesic, Codhydrine, Dekacodin, DH-Codeine,...
- quetiapineQuetiapineQuetiapine , is an atypical antipsychotic approved for the treatment of schizophrenia, and bipolar disorder....
(Seroquel, Ketipinor) - methadoneMethadoneMethadone is a synthetic opioid, used medically as an analgesic and a maintenance anti-addictive for use in patients with opioid dependency. It was developed in Germany in 1937...
Inhibits the metabolism of methadone and raises serum levels. - buprenorphineBuprenorphineBuprenorphine is a semi-synthetic opioid that is used...
Metabolized into norbuprenorphine by cytochrome-P450 isoenzyme 3A4 - Tyrosine kinase inhibitors, including imatinibImatinibImatinib is a drug used to treat certain types of cancer. It is currently marketed by Novartis as Gleevec or Glivec as its mesylate salt, imatinib mesilate . It is used in treating chronic myelogenous leukemia , gastrointestinal stromal tumors and some other diseases...
(Gleevec) and nilotinibNilotinibNilotinib , in the form of the hydrochloride monohydrate salt, is a tyrosine kinase inhibitor approved for the treatment of chronic myelogenous leukemia.-Uses:...
(Tasigna), used to treat chronic myelogenous leukemiaChronic myelogenous leukemiaChronic myelogenous leukemia , also known as chronic granulocytic leukemia , is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of predominantly myeloid cells in the bone marrow and the accumulation of these cells in the blood...
and gastrointestinal stromal tumors. - trazodoneTrazodoneTrazodone is an antidepressant of the serotonin antagonist and reuptake inhibitor class. It is a phenylpiperazine compound...
(Desyrel) Little or no interaction with grapefruit juice. - Anthelmintics (Used for treating certain parasitic infections, includes praziquantelPraziquantelPraziquantel is an anthelmintic effective against flatworms. Praziquantel is not licensed for use in humans in the UK; it is, however, available as a veterinary anthelmintic, and is available for use in humans on a named-patient basis....
albendazoleAlbendazoleAlbendazole, marketed as Albenza, Eskazole, Zentel and Andazol, is a member of the benzimidazole compounds used as a drug indicated for the treatment of a variety of worm infestations. Although this use is widespread in the United States, the U.S. Food and Drug Administration has not approved...
and mebendazoleMebendazoleMebendazole or MBZ is a benzimidazole drug developed by Janssen Pharmaceutica and marketed as Vermox, Ovex, Antiox, and Pripsen...
) - carbamazepineCarbamazepineCarbamazepine is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia...
(Tegretol) Grapefruit or grapefruit juice slows the breakdown of this drug, increasing the level of it in blood - imatinibImatinibImatinib is a drug used to treat certain types of cancer. It is currently marketed by Novartis as Gleevec or Glivec as its mesylate salt, imatinib mesilate . It is used in treating chronic myelogenous leukemia , gastrointestinal stromal tumors and some other diseases...
(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 P-glycoprotein when taken concomitantly with cyclosporine. http://www.gistsupport.org/treatments-for-gist/gleevec/novartis-answers-about-gleevec.php - LoperamideLoperamideLoperamide , a synthetic piperidine derivative, is an opioid drug used against diarrhea resulting from gastroenteritis or inflammatory bowel disease. In most countries it is available generically and under brand names such as Lopex, Imodium, Dimor, Fortasec, and Pepto Diarrhea Control...
(Imodium), the anti-diarrhea drug - colchicineColchicineColchicine is a medication used for gout. It is a toxic natural product and secondary metabolite, originally extracted from plants of the genus Colchicum...
(Colcrys)
Mechanism of the interaction
The CYP3A4 isoform of cytochrome P450 is located in both the liver and the enterocyteEnterocyte
Enterocytes, or intestinal absorptive cells, are simple columnar epithelial cells found in the small intestines and colon. A glycocalyx surface coat contains digestive enzymes. Microvilli on the apical surface increase surface area for the digestion and transport of molecules from the intestinal...
s. Many oral drugs undergo first-pass (presystemic) metabolism by the enzyme. Several organic compounds found in grapefruit and specifically in grapefruit juice exert inhibitory action on drug metabolism by the enzyme. It has been established that a group of compounds called furanocoumarins are responsible for this interaction and not flavonoids as was previously reported.
The list of active furanocoumarins found in grapefruit juice includes: bergamottin
Bergamottin
Bergamottin is a natural furanocoumarin found principally in grapefruit juice. It is also found in the oil of bergamot, from which it was first isolated and from which its name is derived. To a lesser extent, bergamottin is also present in the essential oils of other citrus fruits...
, bergapten
Bergapten
Bergapten is a psoralen found in bergamot essential oil, in other citrus essential oils, and in grapefruit juice. It is the chemical in bergamot oil that causes phototoxicity. Bergapten-free bergamot essential oil or synthetics are now used in perfumery....
, bergaptol and 6',7'-dihydroxybergamottin.
This interaction is particularly dangerous when the drug in question has a low therapeutic index
Therapeutic index
The therapeutic index is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes death or toxicity ....
, so that a small increase in blood concentration can be the difference between therapeutic success and toxicity. Grapefruit juice only inhibits the enzyme within the intestines, not in the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
or elsewhere in the body, and does not impact injected drugs. The degree of the effect varies widely between individuals and between samples of juice, therefore it cannot be accounted for a priori.
Another mechanism of interaction is possibly through the P-glycoprotein
P-glycoprotein
P-glycoprotein 1 also known as multidrug resistance protein 1 or ATP-binding cassette sub-family B member 1 or cluster of differentiation 243 is a glycoprotein that in humans is encoded by the ABCB1 gene...
(Pgp) that is localized in the apical brush border
Brush border
A brush border is the name for the microvilli-covered surface of simple cuboidal epithelium and simple columnar epithelium cells found in certain locations of the body. Microvilli are approximately 100 nanometers in diameter and their length varies from approximately 100 to 2,000 nanometers in...
of the enterocytes. Pgp transports lipophilic
Lipophilic
Lipophilicity, , refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. These non-polar solvents are themselves lipophilic — the axiom that like dissolves like generally holds true...
molecules out of the enterocyte back into the intestinal lumen. Drugs that possess lipophilic properties are either metabolised by CYP3A4 or removed into the intestine by the Pgp transporter. Both the Pgp and CYP3A4 may act synergistically as a barrier to many orally administered drugs. Therefore their inhibition (both or alone) can markedly increase the bioavailability of a drug.
The interaction caused by grapefruit compounds lasts for up to 24 hours and its effect is the greatest when the juice is ingested with the drug or up to 4 hours before the drug.
The flavonoid
Flavonoid
Flavonoids , are a class of plant secondary metabolites....
existing in highest concentration in grapefruit juice is naringin
Naringin
Naringin is a flavanone glycoside. It is a major flavonoid in grapefruit and gives the grapefruit juice its bitter taste. It is metabolized to the flavanone naringenin in humans...
, which in humans is metabolised to naringenin
Naringenin
Naringenin is a flavanone, a type of flavonoid, that is considered to have a bioactive effect on human health as antioxidant, free radical scavenger, anti-inflammatory, carbohydrate metabolism promoter, and immune system modulator. It is the predominant flavanone in grapefruit.-Biological...
. There are also other flavonoids in grapefruit juice, in lower concentrations. Orange juice
Orange juice
Orange juice is a popular beverage made from oranges. It is made by extraction from the fresh fruit, by desiccation and subsequent reconstitution of dried juice, or by concentration of the juice and the subsequent addition of water to the concentrate...
does not contain naringin
Naringin
Naringin is a flavanone glycoside. It is a major flavonoid in grapefruit and gives the grapefruit juice its bitter taste. It is metabolized to the flavanone naringenin in humans...
in as high a concentration, instead containing hesperetin
Hesperetin
Hesperetin is a bioflavonoid and, to be more specific, a flavanone. Hesperidin is water-soluble due to the presence of the sugar part in its structure, so on ingestion it releases its aglycone, i.e, hesperetin....
. It is sometimes recommended as a substitute. Juice of lime
Lime (fruit)
Lime is a term referring to a number of different citrus fruits, both species and hybrids, which are typically round, green to yellow in color, 3–6 cm in diameter, and containing sour and acidic pulp. Limes are a good source of vitamin C. Limes are often used to accent the flavors of foods and...
s and Seville oranges can also inhibit drug metabolism, however, as can apple
Apple
The apple is the pomaceous fruit of the apple tree, species Malus domestica in the rose family . It is one of the most widely cultivated tree fruits, and the most widely known of the many members of genus Malus that are used by humans. Apple grow on small, deciduous trees that blossom in the spring...
juice with some drugs.
| Drug class | Major Interactions | Minor interactions |
|---|---|---|
| Antiarrhythmic agents | amiodarone Amiodarone Amiodarone is an antiarrhythmic agent used for various types of tachyarrhythmias , both ventricular and supraventricular arrhythmias. Discovered in 1961, it was not approved for use in the United States until 1985... (Cordarone) dronedarone Dronedarone Dronedarone is a drug by Sanofi-Aventis, mainly for the indication of cardiac arrhythmias. It was approved by the FDA on July 2, 2009. It is now available as 400 mg tablets in 20, 60 and 100 count packages... (Multaq) |
|
| Antihistamine Antihistamine An H1 antagonist is a histamine antagonist of the H1 receptor that serves to reduce or eliminate effects mediated by histamine, an endogenous chemical mediator released during allergic reactions... s |
terfenadine Terfenadine Terfenadine is an antihistamine formerly used for the treatment of allergic conditions. It was brought to market by Hoechst Marion Roussel and marketed under various brand names including Seldane in the United States, Triludan in the United Kingdom, and Teldane in Australia... (Seldane) (off the market) diphenhydramine Diphenhydramine Diphenhydramine hydrochloride is a first-generation antihistamine possessing anticholinergic, antitussive, antiemetic, and sedative properties which is mainly used to treat allergies. Like most other first-generation antihistamines, the drug also has a powerful hypnotic effect, and for this reason... (Benadryl Benadryl Benadryl is a brand name allergy medicine marketed over-the-counter by Johnson & Johnson subsidiary McNeil Consumer Healthcare. Prior to 2007, Benadryl was marketed by Pfizer Consumer Healthcare... ) (partially) astemizole Astemizole Astemizole was a second generation antihistamine drug which has a long duration of action. Astemizole was discovered by Janssen Pharmaceutica in 1977... (Hismanal) (off the market) |
|
| Calcium channel antagonists | felodipine Felodipine Felodipine is a calcium channel blocker , a drug used to control hypertension . It is marketed under the brand name Plendil by AstraZeneca and Renedil by Sanofi-Aventis... (Plendil) nicardipine Nicardipine Nicardipine hydrochloride is a medication used to treat high blood pressure and angina. It belongs to the class of calcium channel blockers.... (Cardene) nifedipine Nifedipine Nifedipine is a dihydropyridine calcium channel blocker... (Procardia) nimodipine Nimodipine Nimodipine is a dihydropyridine calcium channel blocker originally developed for the treatment of high blood pressure... (Nimotop) nisoldipine Nisoldipine Nisoldipine is a calcium channel blocker of the dihydropyridine class. It sold in the United States under the proprietary name Sular. Nisoldipine has tropism for cardiac blood vessels.... (Sular) isradipine Isradipine Isradipine is a calcium channel blocker of the dihydropyridine class. It is usually prescribed for the treatment of high blood pressure in order to reduce the risk of stroke and heart attack... (DynaCirc) |
|
| Cholesterol Cholesterol Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes... -lowering drugs aka Statin Statin Statins are a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver. Increased cholesterol levels have been associated with cardiovascular diseases, and statins are therefore used in the... s (HMG-CoA reductase inhibitors) |
simvastatin Simvastatin Simvastatin is a hypolipidemic drug used to control elevated cholesterol, or hypercholesterolemia. Simvastatin is a member of the statin class of pharmaceuticals, is a synthetic derivate of a fermentation product of Aspergillus terreus.-Medical uses:The primary uses of simvastatin is for the... (Zocor) lovastatin Lovastatin Lovastatin is a member of the drug class of statins, used for lowering cholesterol in those with hypercholesterolemia and so preventing cardiovascular disease... (Mevacor) |
atorvastatin Atorvastatin Atorvastatin , sold by Pfizer under the trade name Lipitor, is a member of the drug class known as statins, used for lowering blood cholesterol. It also stabilizes plaque and prevents strokes through anti-inflammatory and other mechanisms... (Lipitor) cerivastatin Cerivastatin Cerivastatin is a synthetic member of the class of statins used to lower cholesterol and prevent cardiovascular disease. It was marketed by the pharmaceutical company Bayer A.G. in the late 1990s, competing with Pfizer's highly successful atorvastatin... (Baycol) (off the market) |
| Cough Suppressant/NMDA Antagonist | dextromethorphan Dextromethorphan Dextromethorphan is an antitussive drug. It is one of the active ingredients in many over-the-counter cold and cough medicines, such as Robitussin, NyQuil, Dimetapp, Vicks, Coricidin, Delsym, and others, including generic labels. Dextromethorphan has also found other uses in medicine, ranging... |
|
| Erectile Dysfunction Erectile dysfunction Erectile dysfunction is sexual dysfunction characterized by the inability to develop or maintain an erection of the penis during sexual performance.... drugs |
sildenafil Sildenafil Sildenafil citrate, sold as Viagra, Revatio and under various other trade names, is a drug used to treat erectile dysfunction and pulmonary arterial hypertension . It was originally developed by British scientists and then brought to market by the US-based pharmaceutical company Pfizer... (Viagra) tadalafil Tadalafil Tadalafil is a PDE5 inhibitor, currently marketed in pill form for treating erectile dysfunction under the name Cialis; and under the name Adcirca for the treatment of pulmonary arterial hypertension... (Cialis) vardenafil Vardenafil Vardenafil is a PDE5 inhibitor used for treating erectile dysfunction that is sold under the trade names Levitra and Staxyn.-History:... (Levitra) |
|
| HIV protease inhibitors | saquinavir Saquinavir Saquinavir is an antiretroviral drug used in HIV therapy. It falls in the protease inhibitor class. Two formulations have been marketed:*a hard-gel capsule formulation of the mesylate, with trade name Invirase, which requires combination with ritonavir to increase the saquinavir bioavailability;*a... (Invirase) ritonavir Ritonavir Ritonavir, with trade name Norvir , is an antiretroviral drug from the protease inhibitor class used to treat HIV infection and AIDS.... (Norvir) nelfinavir Nelfinavir Nelfinavir is an antiretroviral drug used in the treatment of the human immunodeficiency virus . Nelfinavir belongs to the class of drugs known as protease inhibitors and like other PIs is generally used in combination with other antiretroviral drugs.Nelfinavir mesylate is a potent and orally... (Viracept) amprenavir (Agenerase) |
|
| Hormone Hormone A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one... s |
ethinyl estradiol (Ortho-Cept, many others) methylprednisolone Methylprednisolone Methylprednisolone is a synthetic glucocorticoid or corticosteroid drug. It is marketed in the USA and Canada under the brand names Medrol and Solu-Medrol. It is also available as a generic drug.... (Medrol) |
|
| Immunosuppressant Immunosuppressant An immunosuppressant is any substance that performs immunosuppression of the immune system. They may be either exogenous, as immunosuppressive drugs, or endogenous, as ,e. g., testosterone... s |
cyclosporine (Sandimmune, Neoral) tacrolimus Tacrolimus Tacrolimus is an immunosuppressive drug that is mainly used after allogeneic organ transplant to reduce the activity of the patient's immune system and so lower the risk of organ rejection... (Prograf) sirolimus Sirolimus Sirolimus , also known as rapamycin, is an immunosuppressant drug used to prevent rejection in organ transplantation; it is especially useful in kidney transplants. A macrolide, sirolimus was first discovered as a product of the bacterium Streptomyces hygroscopicus in a soil sample from Easter... (Rapamune) mercaptopurine Mercaptopurine Mercaptopurine is an immunosuppressive drug.It is a thiopurine.-Uses:... |
|
| Sedative Sedative A sedative or tranquilizer is a substance that induces sedation by reducing irritability or excitement.... s, hypnotic Hypnotic Hypnotic drugs are a class of psychoactives whose primary function is to induce sleep and to be used in the treatment of insomnia and in surgical anesthesia... s, and anxiolytic Anxiolytic An anxiolytic is a drug used for the treatment of anxiety, and its related psychological and physical symptoms... s |
buspirone Buspirone Buspirone is an anxiolytic psychoactive drug of the azapirone chemical class, and is primarily used to treat generalized anxiety disorder Bristol-Myers Squibb gained FDA approval of buspirone in 1986 for treatment of GAD... (Buspar) |
triazolam Triazolam Triazolam is a benzodiazepine drug. It possesses pharmacological properties similar to that of other benzodiazepines, but it is generally only used as a sedative to treat severe insomnia... (Halcion) midazolam Midazolam Midazolam is a short-acting drug in the benzodiazepine class developed by Hoffmann-La Roche in the 1970s. The drug is used for treatment of acute seizures, moderate to severe insomnia, and for inducing sedation and amnesia before medical procedures. It possesses profoundly potent anxiolytic,... (Versed Versed Versed is a book of poetry written by Rae Armantrout and published by Wesleyan University Press in 2009 . It won the National Book Critics Circle Award for Poetry and the 2010 Pulitzer Prize for Poetry.-Awards:... ) diazepam Diazepam Diazepam , first marketed as Valium by Hoffmann-La Roche is a benzodiazepine drug. Diazepam is also marketed in Australia as Antenex. It is commonly used for treating anxiety, insomnia, seizures including status epilepticus, muscle spasms , restless legs syndrome, alcohol withdrawal,... (Valium) zaleplon Zaleplon Zaleplon is a sedative/hypnotic, mainly used for insomnia. It is a nonbenzodiazepine hypnotic from the pyrazolopyrimidine class. In terms of adverse effects zaleplon appears to offer little improvement compared to both benzodiazepines and other non-benzodiazepine Z-drugs.Sonata is manufactured by... (Sonata Sonata Sonata , in music, literally means a piece played as opposed to a cantata , a piece sung. The term, being vague, naturally evolved through the history of music, designating a variety of forms prior to the Classical era... ) alprazolam Alprazolam Alprazolam is a short-acting anxiolytic of the benzodiazepine class of psychoactive drugs. Alprazolam, like other benzodiazepines, binds to specific sites on the GABAA gamma-amino-butyric acid receptor... (Xanax) |
| Other psychotropics | carbamazepine Carbamazepine Carbamazepine is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia... (Tegretol) trazodone Trazodone Trazodone is an antidepressant of the serotonin antagonist and reuptake inhibitor class. It is a phenylpiperazine compound... (Desyrel) quetiapine Quetiapine Quetiapine , is an atypical antipsychotic approved for the treatment of schizophrenia, and bipolar disorder.... (Seroquel) fluvoxamine Fluvoxamine Fluvoxamine is an antidepressant which functions as a selective serotonin reuptake inhibitor . Fluvoxamine was first approved by the U.S. Food and Drug Administration in 1993 for the treatment of obsessive compulsive disorder . Fluvoxamine CR is approved to treat social anxiety disorder... (Luvox) nefazodone Nefazodone Nefazodone is an antidepressant marketed by Bristol-Myers Squibb. Its sale was discontinued in 2003 in some countries due to the rare incidence of hepatotoxicity , which could lead to the need for a liver transplant, or even death. The incidence of severe liver damage is approximately 1 in every... (Serzone) (off the market) |
|
| Other miscellaneous drugs | cisapride Cisapride Cisapride is a gastroprokinetic agent, a drug which increases motility in the upper gastrointestinal tract. It acts directly as a serotonin 5-HT4 receptor agonist and indirectly as a parasympathomimetic. Stimulation of the serotonin receptors increases acetylcholine release in the enteric nervous... (Prepulsid, Propulsid) |