Nutritional properties[edit]

Grapefruit, raw, white, all areas

Nutritional value per 100 g (3.5 oz)

Energy 138 kJ (33 kcal)

Carbohydrates 8.41 g

- Sugars 7.31 g

- Dietary fiber 1.1 g

Fat 0.10 g

Protein 0.69 g

Water 90.48 g

Thiamine (vit. B1) 0.037 mg (3%)

Riboflavin (vit. B2) 0.020 mg (2%)

Niacin (vit. B3) 0.269 mg (2%)

Pantothenic acid (B5) 0.283 mg (6%)

Vitamin B6 0.043 mg (3%)

Folate (vit. B9) 10 μg (3%)

Choline 7.7 mg (2%)

Vitamin C 33.3 mg (40%)

Vitamin E 0.13 mg (1%)

Calcium 12 mg (1%)

Iron 0.06 mg (0%)

Magnesium 9 mg (3%)

Manganese 0.013 mg (1%)

Phosphorus 8 mg (1%)

Potassium 148 mg (3%)

Zinc 0.07 mg (1%)

Link to USDA Database entry

Percentages are roughly approximated

using US recommendations for adults.

Source: USDA Nutrient Database

Grapefruit is an excellent source of many nutrients and phytochemicals that contribute to a healthy diet. Grapefruit is a good source of vitamin C,[19][34] contains the fiber pectin,[35] and the pink and red hues contain the beneficial antioxidant lycopene.[19][36] Studies have shown grapefruit helps lower cholesterol,[19]

[37] and there is evidence that the seeds have antioxidant properties.[38] Grapefruit forms a core part of the "grapefruit diet", the theory being that the fruit's low glycemic index is able to help the body's metabolism burn fat.[39]

Grapefruit seed extract (GSE) has been shown to have strong antimicrobial properties against fungi.[40] It is also believed to have antimicrobial properties for bacteria, however there are no known studies that demonstrate its efficacy. Additionally, although GSE is promoted as a highly effective plant-based preservative by some natural personal care manufacturers, studies have shown that the apparent antimicrobial activity associated with GSE preparations is merely due to contamination with synthetic preservatives.[41][42][43][44][45]

Since grapefruit juice is known to inhibit enzymes necessary for the clearance of some drugs and hormones, some have hypothesized that grapefruit juice may play an indirect role in the development of hormone-dependent cancers. A 2007 study found a correlation between eating a quarter of grapefruit daily and a 30% increase in risk for breast cancer in post-menopausal women. The study points to the inhibition of CYP3A4 enzyme by grapefruit, which metabolizes estrogen.[46] However, a 2008 study has

shown that grapefruit consumption does not increase breast cancer risk and found a significant decrease in breast cancer risk with greater intake of grapefruit in women who never used hormone therapy.[47]

Grapefruit contains large quantities of a simple polyamine called spermidine, which may be related to aging. It is known to be necessary for cell growth and maturation, and as cells age their level of spermidine is known to fall. Scientists have shown that feeding spermidine to worms, fruit flies and yeast significantly prolongs their lifespan. In addition, adding spermidine to the diet of mice decreased molecular markers of aging, and when human immune cells were cultured in a medium containing spermidine, they also lived longer.[48]

Drug interactions[edit]

Main article: Grapefruit drug interactions

Grapefruit can have a number of interactions with drugs,[21] often increasing the effective potency of compounds. Researchers have identified 85 drugs with which grapefruit is known to have an adverse reaction.[22] Grapefruit contains a number of polyphenolic compounds, including theflavanone naringin, alongside the two furanocoumarins bergamottin and dihydroxybergamottin. These inhibit the drug-metabolizing enzyme isoform CYP3A4  predominately in the small intestine, but at higher doses also inhibit hepatic CYP3A4.[23] It is via inhibition of this enzyme that grapefruit increases the effects of a variety of drugs by increasing their bioavailability.[24][25][26][27][28][29] In particular grapefruit and bitter oranges are known to interact with statins.

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.[30] As a result, the amount of the drug in its original form that reaches systemic circulation is reduced due to this first-pass metabolism.

Grapefruit juice contains furanocoumarins. Furanocoumarins irreversibly inhibit a cytochrome P450 metabolizing enzyme called CYP3A4, as stated above. CYP3A4 is a metabolizing enzyme for almost 50% of drugs, and is found in the liver and small intestinal epithelial cells.[31] As a result, many drugs are impacted by consumption of grapefruit 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.[30] An unexpected high dose of the drug in the blood could lead to fatal drug toxicity.[31]

The furanocoumarins found in grapefruit juice are natural chemicals. Thus, they are present in all forms of the fruit including freshly squeezed juice, frozen concentrate, and whole fruit. All these forms of the grapefruit juice have the potential to limit the metabolizing activity of CYP3A4. One whole grapefruit, or a glass of 200mL of grapefruit juice can cause drug overdose toxicity.[2][32]

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. From 2008 to 2012, the percentage of drugs that

interact with grapefruit juice and causes serious harmful effects (gastrointestinal bleeding, nephrotoxicity) has increased from 17 to 43 percent.[2][32]

Interestingly, it seems that the interaction between grapefruit juice and other medication depends on the drug, and not the class of the drug. Drugs that interact with grapefruit juice share 3 common features: they are taken orally, normally only a small amount enters systemic blood circulation, and they are metabolized by CYP3A4.[2]

Although there is an increase in the number of drugs that interact with grapefruit juice, there is a simple way to avoid the drug-food interaction and avoid the harm. Patients should leave a 4 hour gap between taking the medication and grapefruit juice.[31] 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.[31] Because there is a growing number of medications that interact with grapefruit juice,[2] patients should consult a pharmacist or physician before planning to take grapefruit juice with their medications.

Grapefruit juice may be the first drug-interacting fruit juice documented, but apple and orange juices have been also implicated in interfering with 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.[33] Some citrus-based carbonated beverages (e.g., “Sun Drop”) also contain enough grapefruit juice to cause drug interactions, particularly in patients taking cyclosporine.

Unlike other fruits, grapefruit contains a large amount of naringin, and it can take up to 72 hours before the effects of the naringin on the CYP3A4 enzyme are seen. This is particularly problematic due to the fact that only 4 oz of grapefruit contain enough naringin to inhibit the metabolism of substrates of CYP3A4.

Grapefruit and grapefruit juice have been found to interact with numerous drugs (at least 85 by the latest count), in many cases resulting in adverse effects.[1] 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 nofuranocoumarin content, and one is a commercially viable seedless type.[2]

The following drugs are affected by CYP3A4 inhibition with grapefruit compounds:

The benzodiazepines triazolam (Halcion), orally administered midazolam (Versed), orally administered nitrazepam (Mogodon), diazepam (Valium), alprazolam (Xanax) and quazepam (Doral, Dormalin)[3]

ritonavir  (Norvir): Inhibition of CYP3A4 prevents the metabolism of protease inhibitors such as ritonavir.[4]

sertraline  (Zoloft and Lustral)[5]

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.[6][7]

Dihydropyridines  including felodipine (Plendil), nicardipine (Cardene), nifedipine, nisoldipine (Sular) and nitrendipine (Bayotensin)[6]

losartan  (Cozaar)[6]

repaglinide  (Prandin)[6]

verapamil  (Calan SR, Covera HS, Isoptin SR, Verelan)[6]

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.[8]

levothyroxine  (Eltroxin, Levoxyl, Synthroid): the absorption of levothyroxine is affected by grapefruit juice.[clarification needed] [9]

Antiarrhythmics including amiodarone (Cordarone), dronedarone (Multaq), quinidine (Quinidex, Cardioquin, Quinora), disopyramide (Norpace), propafenone (Rythmol) and carvedilol (Coreg)[6]

Erectile dysfunction drugs sildenafil (Viagra), tadalafil (Cialis) and vardenafil (Levitra)[6][10]

The anti-migraine drugs ergotamine (Cafergot, Ergomar), amitryptiline (Elavil, Endep, Vanatrip) and nimodipine (Nimotop)[6]

Fluvoxamine  (Luvox, Faverin, Fevarin and Dumyrox)[11]

Codeine :[12]

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.[13]

omeprazole  (Losec, Prilosec)[14]

zolpidem  (Ambien): Little or no interaction with grapefruit juice.[15]

oxycodone : metabolized by the cytochrome P450 system, specifically CYP3A4, of which the bergamottin flavonoid is a strong inhibitor[16]

quetiapine  (Seroquel)[17]

methadone : Inhibits the metabolism of methadone and raises serum levels.[18]

buprenorphine : Metabolized into norbuprenorphine by cytochrome-P450 isoenzyme 3A4[19]

trazodone  (Desyrel): Little or no interaction with grapefruit juice.[15]

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.[20]

erlotinib  (Tarceva) [21]

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.[22]

Fexofenadine  (Allegra) [23]

Warfarin  (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.).

Mechanism of the interaction[edit]

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 calledfuranocoumarins are responsible for this interaction, and not flavonoids as was previously reported.[24] 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, 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, 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.

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. [25]

Drugs affected by grapefruit juice[26]

Drug class Major Interactions Minor interactions

Antiarrhythmic agentsamiodarone (Cordarone)dronedarone (Multaq)

Antihistamines

terfenadine (Seldane) (off the market)diphenhydramine (Benadryl) (partially)astemizole (Hismanal) (off the market)

Calcium channel antagonists

felodipine (Plendil)nicardipine (Cardene)nifedipine (Procardia)nimodipine (Nimotop)nisoldipine (Sular)isradipine (DynaCirc)

Cholesterol-lowering drugs akaStatins (HMG-CoA reductase inhibitors)

simvastatin (Zocor)lovastatin (Mevacor)

atorvastatin (Lipitor)cerivastatin (Baycol) (off the market)

Cough Suppressant/NMDA Antagonist

dextromethorphan

Erectile Dysfunction drugssildenafil (Viagra)tadalafil (Cialis)vardenafil (Levitra)

HIV protease inhibitors saquinavir (Invirase)ritonavir (Norvir)

nelfinavir (Viracept)amprenavir (Agenerase)

Hormonesethinyl estradiol (Ortho-Cept, many others)methylprednisolone (Medrol)

Immunosuppressants

cyclosporine (Sandimmune, Neoral)tacrolimus (Prograf)sirolimus (Rapamune)mercaptopurine

Sedatives, hypnotics, and anxiolytics

buspirone (Buspar)

triazolam (Halcion)midazolam (Versed)diazepam (Valium)zaleplon (Sonata)alprazolam (Xanax)

Other psychotropics

carbamazepine (Tegretol)trazodone (Desyrel)quetiapine (Seroquel)fluvoxamine (Luvox)nefazodone (Serzone) (off the market)

Other miscellaneous drugs cisapride (Prepulsid, Propulsid)[27]