Grapefruit and grapefruit juice have been found to interact with numerous drugs (at least 85 by the latest[when?] count), in many cases resulting in adverse effects. Organic compounds that are furanocoumarin derivatives interfere with the hepatic and intestinal enzyme cytochrome P450 isoform CYP3A4 and are believed to be primarily responsible for the effects of grapefruit on the enzyme. Bioactive compounds in grapefruit juice may also interfere with P-glycoprotein and organic anion transporting polypeptides (OATPs), either increasing or decreasing the 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. Some grapefruit-pomelo hybrids have practically no furanocoumarin content, and one is a commercially viable seedless type.
The following drugs are affected by CYP3A4 inhibition with grapefruit compounds:
- The benzodiazepines triazolam (Halcion), orally administered midazolam (Versed), orally administered nitrazepam (Mogodon), certain amphetamines (dextroamphetamine, and levoamphetamine), diazepam (Valium), alprazolam (Xanax) and quazepam (Doral, Dormalin)
- ritonavir (Norvir): Inhibition of CYP3A4 prevents the metabolism of protease inhibitors such as ritonavir.
- sertraline (Zoloft and Lustral)
List of Amphetamines That Interact With The Cytochrome P450 CYP2D6 enzyme:
- dextroamphetamine (Dexedrine)
- levoamphetamine (Adderall)
- methamphetamine (Desoxyn)
- Methylphenidate (Ritalin) 
Research has been done on the interaction between amphetamines and The Cytochrome P450 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 such as atorvastatin (Lipitor), lovastatin (Mevacor) and simvastatin (Zocor, Simlup, Simcor, Simvacor); however, pravastatin (Pravachol), fluvastatin (Lescol) and rosuvastatin (Crestor) are unaffected by grapefruit.
- dihydropyridines including felodipine (Plendil), nicardipine (Cardene), nifedipine, nisoldipine (Sular) and nitrendipine (Bayotensin)
- losartan (Cozaar)
- repaglinide (Prandin)
- verapamil (Calan SR, Covera HS, Isoptin SR, Verelan)
- 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.
- levothyroxine (Eltroxin, Levoxyl, Synthroid): the absorption of levothyroxine is affected by grapefruit juice.[clarification needed] 
- Antiarrhythmics including amiodarone (Cordarone), dronedarone (Multaq), quinidine (Quinidex, Cardioquin, Quinora), disopyramide (Norpace), propafenone (Rythmol) and carvedilol (Coreg)
- Erectile dysfunction drugs sildenafil (Viagra), tadalafil (Cialis) and vardenafil (Levitra)
- The anti-migraine drugs ergotamine (Cafergot, Ergomar), amitriptyline (Elavil, Endep, Vanatrip) and nimodipine (Nimotop)
- fluvoxamine (Luvox, Faverin, Fevarin and Dumyrox)
- 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 tacrolimus (Prograf) can also be equally affected for the same reason as cyclosporine, as both drugs are calcineurin inhibitors.
- 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.[unreliable medical source?]
- omeprazole (Losec, Prilosec)
- zolpidem (Ambien): Little or no interaction with grapefruit juice.
- oxycodone: metabolized by the cytochrome P450 system, specifically CYP3A4, of which the bergamottin flavonoid is a strong inhibitor
- quetiapine (Seroquel)
- methadone: Inhibits the metabolism of methadone and raises serum levels.
- buprenorphine: Metabolized into norbuprenorphine by cytochrome-P450 isoenzyme 3A4
- trazodone (Desyrel): Little or no interaction with grapefruit juice.
- anthelmintics: Used for treating certain parasitic infections; includes praziquantel
- 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 P-glycoprotein when taken concomitantly with cyclosporine.
- erlotinib (Tarceva) 
- In a mouse study, blood concentrations of acetaminophen/paracetamol (Tylenol) were found to be increased by white and pink grapefruit juice, with the white juice acting faster.
- fexofenadine (Allegra) 
Mechanism of the interaction
The CYP3A4 isoform of cytochrome P450 is located in both the liver and the enterocytes. 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 effect and toxicity. Grapefruit juice inhibits the enzyme only within the intestines if consumed in low amounts. Intestinal enzyme inhibition will only affect the potency of orally administrated drugs. When larger amounts of grapefruit are consumed it 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 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.
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- 3D structure of CYP2D6 (enzyme that interacts with amphetamines)
- Cytochrome P450 interactions with the CYP2D6
- Dexamfetamine Cytochrome P450 interaction, Structure, and Cyp IAs Vault
- Methylphenidate Cytochrome P450 interaction, Structure, and Cyp IAs Vault
- Appendix 1: Grapefruit Interacting Drugs and Associated Oral Bioavailability, Adverse Event(s), Risk Ranking and Potential Alternative Medications Appendix to: Bailey DG, Dresser G, Arnold JMA. Grapefruit and medication interactions: forbidden fruit or avoidable consequences? CMAJ 2012; doi:10.1503/cmaj.120951. Copyright © 2012 Canadian Medical Association or its licensors
- The Metabolomics Innovation Centre (TMIC)
- Ribbon diagram of the CYP2D6 enzyme structure
- diagram of CYP2D6's ribbon "right foot"-shaped active site cavity
- Schematic diagram of Cytochrome P450 CYP2D6 enzyme
- Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007)
- USDA Database of Flavonoid content of food
- a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions
- a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions.
- SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions.
- Cytochrome P450 CYP2D6 enzyme is responsible for the metabolism of at least 20% of known drugs.
- Grape fruit juice-drug interactions.
- potent inhibition of P450 gene CYP2D6 on d-amphetamine, methylphenidate, and cocaine
- Functional pharmacogenetics of cytochromes P450 involved in drug biotransformation
- Flavonoids and polymer derivatives as CYP3A4 inhibitors for improved oral drug bioavailability.
- methamphetamine-mediated oxidative stress induces astrocyte apoptosis via cytochrome P450 2E1
- Interactions of amphetamine analogs with human liver CYP2D6.
- Drug interactions with grapefruit juice. Extent, probable mechanism and clinical relevance.
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