Some fruit juices and fruits can interact with numerous drugs, in many cases causing adverse effects. The effect was first discovered accidentally, when a test of drug interactions with alcohol used grapefruit juice to hide the taste of the ethanol.
The effect is most studied with grapefruit and grapefruit juice, but similar effects have been observed with certain other citrus fruits. One medical review advises patients to avoid all citrus juices until further research clarifies the risks. Effects have been observed with apple juice, but their clinical significance is not yet known.
One whole grapefruit, or a small glass (200 mL (6.8 US fl oz)) of grapefruit juice, can cause drug overdose toxicity. Fruit consumed three days before the medicine can still have an effect. The relative risks of different types of citrus fruit have not been systematically studied. Affected drugs typically have an auxiliary label saying "Do not take with grapefruit" on the container, and the interaction is elaborated upon in the package insert. People are also advised to ask their physician or pharmacist about drug interactions.
The effects are caused by furanocoumarins (and, to a lesser extent, flavonoids). These chemicals inhibit key drug metabolizing enzymes, such as cytochrome P450 3A4 (CYP3A4). CYP3A4 is a metabolizing enzyme for almost 50% of drugs, and is found in the liver and small intestinal epithelial cells. As a result, many drugs are affected. Inhibition of enzymes can have two different effects, depending on whether the drug is either
- metabolized by the enzyme to an inactive metabolite, or
- activated by the enzyme to an active metabolite.
In the first instance, inhibition of drug-metabolizing enzymes results in elevated concentrations of an active drug in the body, which may cause adverse effects. Conversely, if the medication is a prodrug, it needs to be metabolised to be converted to the active drug. Compromising its metabolism lowers concentrations of the active drug, reducing its therapeutic effect, and risking therapeutic failure.
Low drug concentrations can also be caused when the fruit suppresses drug absorption from the intestine.
The effect of grapefruit juice with regard to drug absorption was originally discovered in 1989. The first published clinical report on grapefruit drug interactions was in 1991 in The Lancet entitled "Interactions of Citrus Juices with Felodipine and Nifedipine." However, the effect only became well-publicized after being responsible for a number of adverse interactions with various medications.
Citrus fruits may contain a number of polyphenol compounds, including the flavonoid naringin and furanocoumarins (such as bergamottin, dihydroxybergamottin, bergapten, and bergaptol). These are natural chemicals. They may be present in all forms of the fruit, including freshly squeezed juice, frozen concentrate, and whole fruit.
Grapefruit, Seville oranges, bergamot, and possibly other citrus also contain large amounts of naringin. It can take up to 72 hours before the effects of the naringin on the CYP3A4 enzyme are seen. This is problematic as a 4-ounce (110 g) portion of grapefruit contains enough naringin to inhibit the metabolism of substrates of CYP3A4. Naringin is a flavonoid which contributes to the bitter flavour of grapefruit.
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Organic compounds that are derivatives of furanocoumarin interfere with liver and intestinal enzyme CYP3A4 and are believed to be primarily responsible for the effects of grapefruit on the enzyme. Cytochrome isoforms affected by grapefruit components also include CYP1A2, CYP2C9, and CYP2D6. Bioactive compounds in grapefruit juice may also interfere with MDR1 (multidrug resistance protein 1) and OATP (organic anion transporting polypeptides), either increasing or decreasing the bioavailability of a number of drugs. Drugs that are metabolized by these enzymes may have interactions with citrus chemicals.
When drugs are taken orally, they enter the gut lumen to be absorbed in the small intestine and sometimes, in the stomach. In order for drugs to be absorbed, they must pass through the epithelial cells that line the lumen wall before they can enter the hepatic portal circulation to be distributed systemically in blood circulation. Drugs are metabolized by drug-specific metabolizing enzymes in the epithelial cells. Metabolizing enzymes transform these drugs into metabolites. The primary purpose for drug metabolism is to detoxify, inactivate, solubilize and eliminate these drugs.[verification needed] As a result, the amount of the drug in its original form that reaches systemic circulation is reduced due to this first-pass metabolism.
Furanocoumarins (see section above) irreversibly inhibit a metabolizing enzyme cytochrome P450 3A4 (CYP3A4). CYP3A4 is a metabolizing enzyme for almost 50% of drugs, and is found in the liver and small intestinal epithelial cells. As a result, many drugs are impacted by consumption of citrus juice. When the metabolizing enzyme is inhibited, less of the drug will be metabolized by it in the epithelial cells. A decrease in drug metabolism means more of the original form of the drug could pass unchanged to systemic blood circulation.[verification needed] An unexpected high dose of the drug in the blood could lead to fatal drug toxicity.
The CYP3A4 is located in both the liver and the enterocytes. Many oral drugs undergo first-pass (presystemic) metabolism by the enzyme. Several organic compounds (see section above) found in citrus and specifically in grapefruit juice exert inhibitory action on drug metabolism by the enzyme.
This interaction is particularly dangerous when the drug in question has a low therapeutic index, so that a small increase in blood concentration can be the difference between therapeutic effect and toxicity. Citrus juice inhibits the enzyme only within the intestines if consumed in small amounts. Intestinal enzyme inhibition will only affect the potency of orally administrated drugs.
When larger amounts are consumed they may also inhibit the enzyme in the liver. The hepatic enzyme inhibition may cause an additional increase in potency and a prolonged metabolic half-life (prolonged metabolic half-life for all ways of drug administration). The degree of the effect varies widely between individuals and between samples of juice, and therefore cannot be accounted for a priori.
Another mechanism of interaction is possibly through the MDR1 (multidrug resistance protein 1) that is localized in the apical brush border of the enterocytes. P-glycoprotein (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.[better source needed][clarification needed]
Duration and timing
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 location of the inhibition occurs in the lining of the intestines, not within the liver. The effects last because grapefruit-mediated inhibition of drug metabolizing enzymes, like CYP3A4, is irreversible; that is, once the grapefruit has "broken" the enzyme, the intestinal cells must produce more of the enzyme to restore their capacity to metabolize drugs that the enzyme is used to metabolize. It takes around 24 hours to regain 50% of the cell's baseline enzyme activity and it can take 72 hours for the enzyme activity to completely return to baseline. For this reason, simply separating citrus consumption and medications taken daily does not avoid the drug interaction.
For medications that interact due to inhibition of OATP (organic anion-transporting polypeptides), a relative short period of time is needed to avoid this interaction, and a 4-hour interval between grapefruit consumption and the medication should suffice. For drugs recently sold on the market, drugs have information pages (monographs) that provide information on any potential interaction between a medication and grapefruit juice. Because there is a growing number of medications that are known to interact with citrus, patients should consult a pharmacist or physician before consuming citrus while taking their medications.
There are three ways to test if a fruit interacts with drugs:
- Test a drug-fruit combination in humans
- Test a fruit chemically for the presence of the interacting polyphenol compounds
- Test a fruit genetically for the genes needed to make the interacting polyphenol compounds
The first approach involves risk to trial volunteers. The first and second approaches have another problem: the same fruit cultivar could be tested twice with different results. Depending on growing and processing conditions, concentrations of the interacting polyphenol compounds can vary dramatically.[better source needed] 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. However, 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. However, many of the citrus cultivars known to be problematic seem to be closely related.
Pomelo (the Asian fruit that was crossed with an orange to produce grapefruit) contains high amounts of furanocoumarin derivatives. Grapefruit relatives and other varieties of pomelo have variable amounts of furanocoumarin.
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.
Both sweet oranges and bitter oranges are mandarin-pomelo hybrids. Bitter oranges (such as the Seville oranges often used in marmalade) can interfere with drugs including etoposide, a chemotherapy drug, some beta blocker drugs used to treat high blood pressure, and cyclosporine, taken by transplant patients to prevent rejection of their new organs. Evidence on sweet oranges is more mixed.
Tests on some tangelos (hybrids of mandarins/tangerines and pomelo or grapefruit) have not shown significant amounts of furanocoumarin; these studies were also conducted on eight fruit all picked at one time from one tree.
Common lemons are the product of orange/citron hybridization, and hence have pomelo ancestry, and although Key limes are papeda/citron hybrids, the more commercially prevalent Persian limes and similar varieties are crosses of the Key lime with lemons, and hence likewise have pomelo ancestry. These limes can also inhibit drug metabolism. Other less-common citrus species also referred to as lemons or limes are genetically distinct from the more common varieties, with different proportions of pomelo ancestry.
Marketing classifications often do not correspond to taxonomic ones. The "Ambersweet" cultivar is classified and sold as an orange, but does not descend from the same common ancestor as sweet oranges; it has grapefruit, orange, and mandarin ancestry. Fruits are often sold as mandarin, tangerine, or satsuma (which may be synonyms). Fruit sold under these names include many which are, like Sunbursts and Murcotts, hybrids with grapefruit ancestry. The diversity of fruits called limes is remarkable; some, like the Spanish lime and Wild lime, are not even citrus fruit.
In some countries, citrus fruit must be labelled with the name of a registered cultivar. Juice is often not so labelled. Some medical literature also names the cultivar tested.
Other fruit and vegetables
The discovery that flavonoids are responsible for some interactions make it plausible that other fruit and vegetables are affected.
Apple juice, especially commercially produced products, interferes with the action of OATPs. This interference can decrease the absorption of a variety of commonly used medications, including beta blockers like atenolol, antibiotics like ciprofloxacin, and antihistamines like montelukast. Apple juice has been implicated in interfering with etoposide, a chemotherapy drug, and cyclosporine, taken by transplant patients to prevent rejection of their new organs.[medical citation needed]
Pomegranate juice inhibits the action of the drug metabolizing enzymes CYP2C9 and CYP3A4. However, as of 2014, 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.
Researchers have identified over 85 drugs with which grapefruit is known to have an adverse reaction. According to a review done by the Canadian Medical Association, there is an increase in the number of potential drugs that can interact with grapefruit juice, and of the number of fruit types that can interact with those drugs. From 2008 to 2012, the number of drugs known to potentially interact with grapefruit, with risk of harmful or even dangerous effects (gastrointestinal bleeding, nephrotoxicity), increased from 17 to 43.
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. However, the effects on the CYP3A4 in the liver could in principle cause interactions with non-oral drugs, and non-CYP3A4-mediated effects also exist.
An easy way to tell if a medication may be affected by grapefruit juice is by researching whether another known CYP3A4 inhibitor drug is already contraindicated with the active drug of the medication in question. Examples of such known CYP3A4 inhibitors include cisapride (Propulsid), erythromycin, itraconazole (Sporanox), ketoconazole (Nizoral), and mibefradil (Posicor).
Incomplete list of affected drugs
Drugs that interact with grapefruit compounds at CYP3A4 include
- benzodiazepines: triazolam (Halcion), orally administered midazolam (Versed), orally administered nitrazepam (Mogodon), diazepam (Valium), clonazepam (Klonopin), 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 grapefruit compounds at CYP1A2 include
Drugs that interact with grapefruit compounds at CYP2D6 include
Research has been done on the interaction between amphetamines and CYP2D6 enzyme, and researchers concluded that some parts of substrate molecules contribute to the binding of the enzyme.
Additional drugs found to be affected by grapefruit juice include, but are not limited to
- Some statins, including atorvastatin (Lipitor), lovastatin (Mevacor), and simvastatin (Zocor, Simlup, Simcor, Simvacor)
- Anti-arrhythmics including amiodarone (Cordarone), dronedarone (Multaq), quinidine (Quinidex, Cardioquin, Quinora), disopyramide (Norpace), propafenone (Rythmol) and carvedilol (Coreg)
- Amlodipine: 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 drugs sildenafil (Viagra), tadalafil (Cialis) and vardenafil (Levitra)
- Acetaminophen/paracetamol (Tylenol) concentrations were found to be increased in murine blood by 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.
- Anthelmintics: Used for treating certain parasitic infections; includes praziquantel
- Apremilast (Otezla): Used to treat psoriasis.[failed verification]
- Buprenorphine: Metabolized into norbuprenorphine by CYP3A4
- Buspirone (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 entirely by CYP2D6.
- Ciclosporin (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 (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 which 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.
- 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."[clarification needed]
- Losartan (Cozaar)
- Methadone: Inhibits the metabolism of methadone and raises serum levels.
- Omeprazole (Losec, Prilosec)
- Oxycodone: grapefruit juice enhances the exposure to oral oxycodone. And 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 and 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)
- 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)
- Warfarin (coumadin)
- Zolpidem (Ambien): Little or no interaction with grapefruit juice.
- Bailey, D. G.; Dresser, G.; Arnold, J. M. O. (2013). "Grapefruit-medication interactions: Forbidden fruit or avoidable consequences?". Canadian Medical Association Journal. 185 (4): 309–316. doi:10.1503/cmaj.120951. PMC 3589309. PMID 23184849.
- Bailey, David G.; Malcolm, J.; Arnold, O.; David Spence, J. (4 January 2002). "Grapefruit juice-drug interactions". British Journal of Clinical Pharmacology. 46 (2): 101–110. doi:10.1046/j.1365-2125.1998.00764.x. PMC 1873672. PMID 9723817.
- Bailey, D.G.; Dresser, G.K.; Bend, J.R. (June 2003). "Bergamottin, lime juice, and red wine as inhibitors of cytochrome P450 3a4 activity: comparison with grapefruit juice". Clinical Pharmacology & Therapeutics. 73 (6): 529–537. doi:10.1016/S0009-9236(03)00051-1. PMID 12811362.
- Gallagher, James (26 November 2012). "Grapefruit and pills mix warning". BBC News.
- Chen, M.; Zhou, S. Y.; Fabriaga, E.; Zhang, P. H.; Zhou, Q. (April 2018). "Food-drug interactions precipitated by fruit juices other than grapefruit juice: An update review". J Food Drug Anal. 26 (2S): S61–S71. doi:10.1016/j.jfda.2018.01.009. PMID 29703387.
- Saito, Mitsuo; Hirata-Koizumi, Mutsuko; Matsumoto, Mariko; Urano, Tsutomu; Hasegawa, Ryuichi (2005). "Undesirable effects of citrus juice on the pharmacokinetics of drugs: focus on recent studies". Drug Safety. 28 (8): 677–694. doi:10.2165/00002018-200528080-00003. PMID 16048354.
- "Fruit juice 'could affect drugs'". BBC News. 20 August 2008.
- "Dr. David Bailey finds new reason to avoid fruit juices when taking drugs - Dr. David Bailey finds new reason to avoid fruit juices when taking drugs - Western University".
- Greenblatt DJ, von Moltke LL, Harmatz JS, et al. (August 2003). "Time course of recovery of cytochrome p450 3A function after single doses of grapefruit juice". Clinical Pharmacology and Therapeutics. 74 (2): 121–9. doi:10.1016/S0009-9236(03)00118-8. PMID 12891222.
- Mitchell, Steve (19 February 2016). "Why Grapefruit and Medication Can Be a Dangerous Mix". Consumer Reports. Retrieved 4 May 2016.
- Fuhr, Uwe (1998). "Drug Interactions with Grapefruit Juice: Extent, Probable Mechanism and Clinical Relevance". Drug Safety. 18 (4): 251–272. doi:10.2165/00002018-199818040-00002. ISSN 0114-5916. PMID 9565737.
- Pirmohamed, Munir (12 January 2013). "Drug-grapefruit juice interactions: Two mechanisms are clear but individual responses vary". BMJ. 346 (7890): 9. doi:10.1136/bmj.f1. PMID 23297175.
- FDA Consumer update
- Bailey, D. G.; Spence, J. D.; Munoz, C.; Arnold, J. M. (1991). "Interaction of citrus juices with felodipine and nifedipine". The Lancet. 337 (8736): 268–269. doi:10.1016/0140-6736(91)90872-m. PMID 1671113.
- Bakalar, Nicholas (21 March 2006). "Experts Reveal the Secret Powers of Grapefruit Juice". The New York Times.
- Edwards, D. J.; Bernier, S. M. (1996). "Naringin and naringenin are not the primary CYP3A inhibitors in grapefruit juice". Life Sciences. 59 (13): 1025–1030. doi:10.1016/0024-3205(96)00417-1. PMID 8809221.
- Calvarano M, Postorino E, Gionfriddo F, Calvarano I, Bovalo F, Calabro G (1 September 1996). "Naringin Extraction from Exhausted Bergamot Peels". Perfumer & Flavourist. Retrieved 19 August 2017.
- Paine, M.F.; Widmer, W.W.; Hart, H.L.; Pusek, S.N.; Beavers, K.L.; Criss, A.B.; Brown, S.S.; Thomas, B.F.; Watkins, P.B. (May 2006). "A furanocoumarin-free grapefruit juice establishes furanocoumarins as the mediators of the grapefruit juice-felodipine interaction". The American Journal of Clinical Nutrition. 83 (5): 1097–105. doi:10.1093/ajcn/83.5.1097. PMID 16685052.
- Veronese ML, Gillen LP, Burke JP, Dorval EP, Hauck WW, Pequignot E, Waldman SA, Greenberg HE. Exposure-dependent inhibition of intestinal and hepatic CYP3A4 in vivo by grapefruit juice. Journal of Clinical Pharmacology. 2003;43(8):831–9. doi:10.1177/0091270003256059. PMID 12953340.
- Tassaneeyakul W, Guo LQ, Fukuda K, Ohta T, Yamazoe Y (June 2000). "Inhibition selectivity of grapefruit juice components on human cytochromes P450". Archives of Biochemistry and Biophysics. 378 (2): 356–63. doi:10.1006/abbi.2000.1835. PMID 10860553.
- He K, Iyer KR, Hayes RN, Sinz MW, Woolf TF, Hollenberg PF (April 1998). "Inactivation of cytochrome P450 3A4 by bergamottin, a component of grapefruit juice". Chemical Research in Toxicology. 11 (4): 252–9. doi:10.1021/tx970192k. PMID 9548795.
- Bailey DG, Malcolm J, Arnold O, Spence JD (August 1998). "Grapefruit juice–drug interactions". British Journal of Clinical Pharmacology. 46 (2): 101–10. doi:10.1046/j.1365-2125.1998.00764.x. PMC 1873672. PMID 9723817.
- Garg SK, Kumar N, Bhargava VK, Prabhakar SK (September 1998). "Effect of grapefruit juice on carbamazepine bioavailability in patients with epilepsy". Clinical Pharmacology and Therapeutics. 64 (3): 286–8. doi:10.1016/S0009-9236(98)90177-1. PMID 9757152.
- Bailey DG, Dresser GK (2004). "Interactions between grapefruit juice and cardiovascular drugs". American Journal of Cardiovascular Drugs. 4 (5): 281–97. doi:10.2165/00129784-200404050-00002. PMID 15449971.
- Bressler R (November 2006). "Grapefruit juice and drug interactions. Exploring mechanisms of this interaction and potential toxicity for certain drugs". Geriatrics. 61 (11): 12–8. PMID 17112309.
- Pandit Introduction to Pharmaceutical Sciences
- Veronese ML, Gillen LP, Burke JP, et al. (August 2003). "Exposure-dependent inhibition of intestinal and hepatic CYP3A4 in vivo by grapefruit juice". Journal of Clinical Pharmacology. 43 (8): 831–9. doi:10.1177/0091270003256059. PMID 12953340.
- Bailey, David G. (November 2010). "Fruit juice inhibition of uptake transport: a new type of food-drug interaction". British Journal of Clinical Pharmacology. 70 (5): 645–655. doi:10.1111/j.1365-2125.2010.03722.x. PMC 2997304. PMID 21039758.
- Lundahl J, Regårdh CG, Edgar B, Johnsson G (1995). "Relationship between time of intake of grapefruit juice and its effect on pharmacokinetics and pharmacodynamics of felodipine in healthy subjects". European Journal of Clinical Pharmacology. 49 (1–2): 61–7. doi:10.1007/BF00192360. PMID 8751023.
- Bailey, David G.; Dresser, George; Arnold, J. Malcolm O. (5 March 2013). "Grapefruit–medication interactions: Forbidden fruit or avoidable consequences?". CMAJ : Canadian Medical Association Journal. 185 (4): 309–316. doi:10.1503/cmaj.120951. ISSN 0820-3946. PMC 3589309. PMID 23184849.
- Greenblatt, DJ; Patki, KC; von Moltke, LL; Shader, RI (2001). "Drug interactions with grapefruit juice: an update". J Clin Psychopharmacol. 21 (4): 357–9. doi:10.1097/00004714-200108000-00001. PMID 11476118.
- Chen, Chunxian; Yu, Qibin; Wei, Xu; Cancalon, Paul F.; Gmitter Jr., Fred G.; Belzile, F. (October 2014). "Identification of genes associated with low furanocoumarin content in grapefruit". Genome. 57 (10): 537–545. doi:10.1139/gen-2014-0164. PMID 25756876.
- "Important considerations for grapefruit and drug interaction".
- Curk, Franck; Ollitrault, Frédérique; Garcia-Lor, Andres; Luro, François; Navarro, Luis; Ollitrault, Patrick (2016). "Phylogenetic origin of limes and lemons revealed by cytoplasmic and nuclear markers". Annals of Botany. 11 (4): 565–583. doi:10.1093/aob/mcw005. PMC 4817432. PMID 26944784.
- Wu, Guohong Albert; Terol, Javier; Ibanez, Victoria; López-García, Antonio; Pérez-Román, Estela; Borredá, Carles; Domingo, Concha; Tadeo, Francisco R; Carbonell-Caballero, Jose; Alonso, Roberto; Curk, Franck; Du, Dongliang; Ollitrault, Patrick; Roose, Mikeal L. Roose; Dopazo, Joaquin; Gmitter Jr, Frederick G.; Rokhsar, Daniel; Talon, Manuel (2018). "Genomics of the origin and evolution of Citrus". Nature. 554 (7692): 311–316. doi:10.1038/nature25447. PMID 29414943.
- Curk, Franck; Ancillo, Gema; Garcia-Lor, Andres; Luro, François; Perrier, Xavier; Jacquemoud-Collet, Jean-Pierre; Navarro, Luis; Ollitrault, Patrick (December 2014). "Next generation haplotyping to decipher nuclear genomic interspecific admixture in Citrusspecies: analysis of chromosome 2". BMC Genetics. 15 (1): 152. doi:10.1186/s12863-014-0152-1. PMC 4302129. PMID 25544367.
- Widmer, Wilbur (31 May 2006). "One Tangerine/Grapefruit Hybrid (Tangelo) Contains Trace Amounts of Furanocoumarins at a Level Too Low To Be Associated with Grapefruit/Drug Interactions". Journal of Food Science. 70 (6): c419–c422. doi:10.1111/j.1365-2621.2005.tb11440.x.
- "Hybrid grapefruit safe for prescription meds". Futurity.org. 25 October 2011. Retrieved 28 January 2013.
- Bakalar, Nicholas (21 March 2006). "Experts Reveal the Secret Powers of Grapefruit Juice". The New York Times. p. F6. Retrieved 21 November 2006.
- "Synonymy of C. reticulata at The Plant List".
- Larry K. Jackson and Stephen H. Futch (10 July 2018). "Robinson Tangerine". ufl.edu.
- Commernet, 2011. "20-13.0061. Sunburst Tangerines; Classification and Standards, 20-13. Market Classification, Maturity Standards And Processing Or Packing Restrictions For Hybrids, D20. Departmental, 20. Department of Citrus, Florida Administrative Code". State of Florida. Retrieved 14 May 2015.
- Andrade, Chittaranjan (24 November 2014). "Fruit Juice, Organic Anion Transporting Polypeptides, and Drug Interactions in Psychiatry". The Journal of Clinical Psychiatry. 75 (11): e1323–e1325. doi:10.4088/JCP.14f09572. PMID 25470100.
- Andrade, Chittaranjan (15 April 2014). "Potentially Significant Versus Clinically Significant Drug Interactions: Pomegranate Juice as a Case in Point". The Journal of Clinical Psychiatry. 75 (4): e292–e293. doi:10.4088/JCP.14f09112. PMID 24813412.
- Rabin, Roni Caryn (17 December 2012). "Grapefruit Is a Culprit in More Drug Reactions". The New York Times.
- "Wake Forest Baptist Medical Center" (PDF). wakehealth.edu.
- Musmul, A.; Cingi, M. Ipek; Boydaĝ, B. S.; Aktan, Yasemın; Özdemir, Murat (1998). "Interaction between grapefruit juice and diazepam in humans". European Journal of Drug Metabolism and Pharmacokinetics. 23: 55–59. doi:10.1007/BF03189827. PMID 9625273. S2CID 9055484.
- "Drug Interactions Checker - Medscape Drug Reference Database". reference.medscape.com. Retrieved 6 March 2019.
- Tanaka, E. (October 1999). "Clinically significant pharmacokinetic drug interactions with benzodiazepines". Journal of Clinical Pharmacy and Therapeutics. 24 (5): 347–355. doi:10.1046/j.1365-2710.1999.00247.x. ISSN 0269-4727. PMID 10583697.
- Sugimoto K, Araki N, Ohmori M, et al. (March 2006). "Interaction between grapefruit juice and hypnotic drugs: comparison of triazolam and quazepam". European Journal of Clinical Pharmacology. 62 (3): 209–15. doi:10.1007/s00228-005-0071-1. PMID 16416305.
- Wu D, Otton SV, Inaba T, Kalow W, Sellers EM (June 1997). "Interactions of amphetamine analogs with human liver CYP2D6". Biochemical Pharmacology. 53 (11): 1605–12. doi:10.1016/S0006-2952(97)00014-2. PMID 9264312.
- "Ritonavir (Norvir)". HIV InSite. UCSF. 18 October 2006. Retrieved 12 March 2008.[failed verification]
- Lee AJ, Chan WK, Harralson AF, Buffum J, Bui BC (November 1999). "The effects of grapefruit juice on sertraline metabolism: an in vitro and in vivo study". Clinical Therapeutics. 21 (11): 1890–9. doi:10.1016/S0149-2918(00)86737-5. PMID 10890261.
- Pillai, Unnikrishnan; Muzaffar, Jameel; Sen, Sandeep; Yancey, Abigail (2009). "Grapefruit Juice and Verapamil: A Toxic Cocktail". Southern Medical Journal. 102 (3): 308–309. doi:10.1097/smj.0b013e3181928f81. PMID 19204629. Retrieved 22 January 2017.
- Fuhr, Uwe (1998). "Drug Interactions with Grapefruit Juice". Drug Safety. 18 (4): 251–272. doi:10.2165/00002018-199818040-00002. PMID 9565737.
- Preissner S, Kroll K, Dunkel M, et al. (January 2010). "SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions". Nucleic Acids Research. 38 (Database issue): D237–43. doi:10.1093/nar/gkp970. PMC 2808967. PMID 19934256.
- Shah A, Kumar S, Simon SD, Singh DP, Kumar A (2013). "HIV gp120- and methamphetamine-mediated oxidative stress induces astrocyte apoptosis via cytochrome P450 2E1". Cell Death & Disease. 4 (10): e850. doi:10.1038/cddis.2013.374. PMC 3824683. PMID 24113184.
- "Metabolism/ Metabolites of amphetamines interacting with The Cytochrome P450 CYP2D6 enzyme". U.S. National Library of Medicine.[verification needed]
- Lilja JJ, Kivistö KT, Neuvonen PJ (August 1999). "Grapefruit juice increases serum concentrations of atorvastatin and has no effect on pravastatin". Clinical Pharmacology and Therapeutics. 66 (2): 118–27. doi:10.1053/cp.1999.v66.100453001. PMID 10460065.
- Bailey DG, Dresser GK (2004). "Interactions between grapefruit juice and cardiovascular drugs". American Journal of Cardiovascular Drugs. 4 (5): 281–97. doi:10.2165/00129784-200404050-00002. PMID 15449971.
- Jetter A, Kinzig-Schippers M, Walchner-Bonjean M, et al. (January 2002). "Effects of grapefruit juice on the pharmacokinetics of sildenafil". Clinical Pharmacology and Therapeutics. 71 (1): 21–9. doi:10.1067/mcp.2002.121236. PMID 11823754.
- Dasgupta A, Reyes MA, Risin SA, Actor JK (December 2008). "Interaction of white and pink grapefruit juice with acetaminophen (paracetamol) in vivo in mice". Journal of Medicinal Food. 11 (4): 795–8. doi:10.1089/jmf.2008.0059. PMID 19053875.
- Qinna, Nidal A.; Ismail, Obbei A.; Alhussainy, Tawfiq M.; Idkaidek, Nasir M.; Arafat, Tawfiq A. (1 April 2016). "Evidence of reduced oral bioavailability of paracetamol in rats following multiple ingestion of grapefruit juice". European Journal of Drug Metabolism and Pharmacokinetics. 41 (2): 187–195. doi:10.1007/s13318-014-0251-4. PMID 25547640.
- Samojlik, I.; Rasković, A.; Daković-Svajcer, K.; Mikov, M.; Jakovljević, V. (1 July 1999). "The effect of paracetamol on peritoneal reflex after single and multiple grapefruit ingestion". Experimental and Toxicologic Pathology. 51 (4–5): 418–420. doi:10.1016/S0940-2993(99)80032-3. PMID 10445408.
- Falat, Frank (June 2015). "Grapefruit Drug Interactions – Dangerous Mixing Grapefruit". Five Hour Diabetic. Retrieved 25 February 2016.
- "OTEZLA Product Monograph" (PDF). Celgene Canada. Celgene Corporation. 12 November 2014. Archived from the original (PDF) on 7 April 2015. Retrieved 3 April 2015.
- Elkader A, Sproule B (2005). "Buprenorphine: clinical pharmacokinetics in the treatment of opioid dependence". Clinical Pharmacokinetics. 44 (7): 661–80. doi:10.2165/00003088-200544070-00001. PMID 15966752.
- Lilja JJ, Kivistö KT, Backman JT, Lamberg TS, Neuvonen PJ (December 1998). "Grapefruit juice substantially increases plasma concentrations of buspirone". Clinical Pharmacology and Therapeutics. 64 (6): 655–60. doi:10.1016/S0009-9236(98)90056-X. PMID 9871430.
- Smith, Howard S. (1 July 2009). "Opioid Metabolism". Mayo Clinic Proceedings. 84 (7): 613–624. doi:10.4065/84.7.613. PMC 2704133. PMID 19567715.
- Paine MF, Widmer WW, Pusek SN, et al. (April 2008). "Further characterization of a furanocoumarin-free grapefruit juice on drug disposition: studies with cyclosporine". The American Journal of Clinical Nutrition. 87 (4): 863–71. doi:10.1093/ajcn/87.4.863. PMID 18400708.
- "HIGHLIGHTS OF PRESCRIBING INFORMATION" (PDF). Gene. Retrieved 28 January 2013.
- Burnett, Bruce (1 September 2014). "Exemestane (Aromasin)". Macmillan Cancer Support. Retrieved 17 July 2017.
- Dresser GK, Kim RB, Bailey DG (March 2005). "Effect of grapefruit juice volume on the reduction of fexofenadine bioavailability: possible role of organic anion transporting polypeptides". Clinical Pharmacology and Therapeutics. 77 (3): 170–7. doi:10.1016/j.clpt.2004.10.005. PMID 15735611.
- Yael Waknine (1 January 2007). "FDA Safety Changes: Allegra, Cymbalta, Concerta". Medscape Medical News.
- Hori H, Yoshimura R, Ueda N, et al. (August 2003). "Grapefruit juice-fluvoxamine interaction--is it risky or not?". Journal of Clinical Psychopharmacology. 23 (4): 422–4. doi:10.1097/01.jcp.0000085423.74359.f2. PMID 12920426.
- Jhaveri, Limca. "Novartis Answers About Gleevec". GIST Support International. Archived from the original on 23 January 2011. Retrieved 31 December 2010.
- Peltoniemi, Marko A.; Saari, Teijo I.; Hagelberg, Nora M.; Laine, Kari; Neuvonen, Pertti J.; Olkkola, Klaus T. (June 2012). "S-ketamine concentrations are greatly increased by grapefruit juice". European Journal of Clinical Pharmacology. 68 (6): 979–986. doi:10.1007/s00228-012-1214-9. ISSN 1432-1041. PMID 22286159.
- Lilja JJ, Laitinen K, Neuvonen PJ (September 2005). "Effects of grapefruit juice on the absorption of levothyroxine". British Journal of Clinical Pharmacology. 60 (3): 337–41. doi:10.1111/j.1365-2125.2005.02433.x. PMC 1884777. PMID 16120075.
- Benmebarek M, Devaud C, Gex-Fabry M, et al. (July 2004). "Effects of grapefruit juice on the pharmacokinetics of the enantiomers of methadone". Clinical Pharmacology and Therapeutics. 76 (1): 55–63. doi:10.1016/j.clpt.2004.03.007. PMID 15229464.
- Mouly S, Paine MF (August 2001). "Effect of grapefruit juice on the disposition of omeprazole". British Journal of Clinical Pharmacology. 52 (2): 216–7. doi:10.1111/j.1365-2125.1978.00999.pp.x. PMC 2014525. PMID 11488783.
- Nieminen, Tuija H.; Hagelberg, Nora M.; Saari, Teijo I.; Neuvonen, Mikko; Neuvonen, Pertti J.; Laine, Kari; Olkkola, Klaus T. (1 October 2010). "Grapefruit juice enhances the exposure to oral oxycodone". Basic & Clinical Pharmacology & Toxicology. 107 (4): 782–788. doi:10.1111/j.1742-7843.2010.00582.x. PMID 20406214.
- "Grapefruit Interactions" (PDF). healthCentral. Archived from the original (PDF) on 18 November 2012. Retrieved 28 January 2013.
- Beverage JN, Sissung TM, Sion AM, Danesi R, Figg WD (September 2007). "CYP2D6 polymorphisms and the impact on tamoxifen therapy". Journal of Pharmaceutical Sciences. 96 (9): 2224–31. doi:10.1002/jps.20892. PMID 17518364.
- "Grapefruit and medication: A cautionary note". Harvard Medical School Family Health Guide. February 2006. Retrieved 28 January 2013.
- 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
- Gross AS, Goh YD, Addison RS, Shenfield GM (April 1999). "Influence of grapefruit juice on cisapride pharmacokinetics". Clinical Pharmacology and Therapeutics. 65 (4): 395–401. doi:10.1016/S0009-9236(99)70133-5. PMID 10223776.
- "Corlanor (ivabradine) dose, indications, adverse effects, interactions..." PDR.net.