Grapefruit

Scientific Name(s): Citrus paradisi Macfad. Family: Rutaceae

Common Name(s): Grapefruit

Clinical Overview

Uses of Grapefruit

Grapefruit juice is used as a nutritional supplement to counteract potassium loss. Grapefruit pectin can reduce cholesterol and promote regression of atherosclerosis. Other effects include induction of red cell aggregation by constituent naringin, reduction of hemocrits and possible anti-cancer effects.

Grapefruit Dosing

Grapefruit juice has been given in clinical studies from 1 to 9 glasses daily, or 240 mL of double-strength juice twice daily.

Contraindications

Contraindicated in patients taking medication which is metabolized by liver/cytochrome P450 3A4 (CYP3A4) enzyme system (see Interactions).

Pregnancy/Lactation

Generally recognized as safe or used as food. Safety and efficacy for dosages above those in foods are unproven and should be avoided.

Grapefruit Interactions

Grapefruit juice increases intestinal cell wall metabolism (CYP3A4) of albendazole, amiodarone, benzodiazepines (ie, midazolam and triazolam), buspirone, calcium channel blockers (including amlodipine, diltiazem, felodipine, nicardipine, nifedipine, nimodipine, nisoldipine, and verapamil), carbamazepine, cisapride, clomipramine, cyclosporine, dextromethorphan, estrogens (eg, estrone and ethinyl estradiol), fluvoxamine, HMG-CoA reductase inhibitors (eg, atorvastatin, lovastatin, simvastatin but not pravastatin), losartan, macrolide antibiotics (eg, clarithromycin, erythromycin), pimozide, praziquantel, quinidine, saquinavir, and scopolamine. Plasma concentrations of digoxin and sildenafil may be increased; while plasma concentrations of amprenavir, etoposide, fexofenadine, and itraconazole may be decreased. Grapefruit juice appears to delay both the absorption of indinavir and the time to reach peak plasma concentrations of indinavir and quinidine. It would be prudent to advise patients to take these medications with a liquid other than grapefruit juice and to avoid grapefruit juice.

Grapefruit Adverse Reactions

A case report exists about grapefruit juice-induced hypotension.

Toxicology

Grapefruit juice can create adverse effects by altering drugs metabolized by the CYP3A4 enzyme system (eg, some nonsedating antihistamines, benzodiazepines, selected calcium channel blockers, estrogens, quinidine, and cyclosporine).

Botany

The grapefruit is a large, dimpled, round citrus fruit, measuring 3 to 6 inches in diameter. It descends from a cross between a pomelo (pummelo) or shaddock ( C. grandis ), a large Malaysian citrus, and a sweet orange. Others believe the grapefruit may have arisen as a mutation of another type of citrus tree. The fruit grows in clusters similar to grapes, and this may be the reason why the “grapefruit” was so named. The two main varieties of grapefruit include the Duncan (many seeds and good flavor) and the Marsh (seedless with less flavor). The pink varieties followed; the Foster (1907; seeded) and the Thompson (1913; seedless). The Ruby red-pulped grapefruit was developed in the late twenties in McAllen, Texas. Grapefruits can be considered a “New World” product, a species only a few hundred years old. 1 , 2 , 3 The juice of the fruit, including concentrate, accounts for approximately 42% of all US processed grapefruit products. 2

History

In 1310 B.C., Greek historian Theophrastus wrote of how Citron was thought to be an antidote to poison and how it could also “sweeten the breath.” Later, Pliny, a Roman naturalist, used the word “citrus” for the first time and labeled the fruit as a medicine. 4 The grapefruit, then called “small shaddock,” was first mentioned by Griffith Hughes in 1750, as the “forbidden fruit” of Barbados. 1 , 2 The name “grapefruit” was said to have been first used in Jamaica in 1814. In 1823, the grapefruit was introduced in Florida by a French count, Odette Phillippe, but did not begin to gain popularity until the end of the nineteenth century. 1 Worldwide production of grapefruit today averages 4.3 million metric tons. 2

In the 1930's, Hollywood's “Grapefruit Diet” came into vogue, including limitation of calorie intake to approximately 800 per day, and including grapefruit consumption at each meal. Weight can be lost on this diet, but any diet based primarily on one food is too restrictive to be healthy because too many important nutrients may be missing. 5

Analysis of grapefruit seed extract has been performed. 6

Chemistry

The chemistry of citrus fruits has been reviewed. Components of citrus fruits include sugars, polysaccharides, organic acids, nitrogenous constituents, lipids, carotenoids (that contribute to color), vitamins, minerals, flavonoids and volatile components (that contribute to aroma). 7 , 8

Grapefruit is high in water and fiber. 5 The whole fruit is also a good source of potassium, vitamin C, inositol, bioflavonoids and pectin. 2 However, the juice alone is not high in pectin. 4 In addition, grapefruit has no fat and is low in calories and sodium. The pink variety contains beta-carotene. 5 Folic acid is also present in grapefruit. The peel contains citral, an aldehyde that antagonizes the effects of vitamin A. 2

Other constituents in grapefruit have been found to affect liver enzymes. 6′,7′-dihydroxybergamottin, a cytochrome P450 inhibitor, has been identified. 9 Naringin, naringenin, limonin and obacunone also exhibit inhibitory effects in human liver microsomes (see Pharmacology). 10

Grapefruit Uses and Pharmacology

In the US, the grapefruit is popular as a breakfast fruit, usually eaten in halves. Approximately 50% of the world grapefruit crop is made into juice. 2

Nutrition studies have been performed that discovered grapefruit to be of value as a dietary supplement. 11 Grapefruit has also been used as a nutritional supplement for patients experiencing potassium loss. 12

Research reveals no animal or clinical data regarding the use of grapefruit as a nutritional supplement.

Grapefruit pectin has been found to reduce cholesterol and to promote regression of atherosclerosis. 4 , 13 Because the pectin resides in the cell walls of the fruit and not in the juice, the juice itself does not decrease blood cholesterol. 4

Research reveals no animal or clinical data regarding the use of grapefruit for cholesterol lowering effects.

Other blood effects of grapefruit include induction of red cell aggregation by constituent naringin in vitro and reduction of hematocrits in 36 human subjects who ingested one grapefruit per day. 14

The Swedes have studied grapefruit for its anti-cancer effects. In a 1986 analysis, subjects who consumed citrus fruit daily had lower incidences of pancreatic cancer. 2

A pharmacokinetic study suggests citrus flavanones undergo glucuronidation before urinary excretion. 15

A report discussing treatment of psoriasis with cyclosporine and grapefruit juice is available. 16

Grapefruit juice has been found to increase the bioavailability of certain drugs by inhibition of the cytochrome P450 3A4 (CYP3A4) isozyme found in the liver and gut wall. 17 , 18 , 19 , 20 , 21 The effects of grapefruit juice are primarily on the isozyme found in the gut wall. As a result of this inhibition, more drug is absorbed and the plasma concentration increases. The elevated drug concentration may lead to an increase in the drug's activity and side effects. In some instances, the increase in drug concentration may be beneficial (see Toxicology).

Dosage

Grapefruit juice has been given in clinical studies from 1-9 glasses daily, or 240 mL of double-strength juice twice daily. 22 , 23

Pregnancy/Lactation

Generally recognized as safe or used as food. Safety and efficacy for dosages above those in foods unproven and should be avoided.

Interactions

Grapefruit juice has been reported to interact with numerous drugs. Most studies of grapefruit juice interactions have involved controlled trials in healthy volunteers ingesting the study drug with water and regular- or double-strength grapefruit juice. The mechanism of the majority of these interactions involves inhibition of the cytochrome P450 3A4 (CYP3A4) in the small intestine, which may elevate drug plasma concentrations and increase the risk of side effects. After a 10 oz glass of grapefruit juice the recovery half-life for CYP3A4 activity is approximately 23 hours. 24 Recovery is almost complete within 3 days. In addition, grapefruit juice may decrease or delay drug absorption. In other cases, the mechanism of reported interactions is unknown. Following is a listing of grapefruit-drug interactions categorized on the basis of the best available documentation.

Drug plasma concentrations increased by grapefruit juice, probably due to inhibition of metabolism (CYP3A4) in the small intestine:

• albendazole 25
• amiodarone 26
• amlodipine 27 , 28
• atorvastatin 29
• buspirone 30
• carbamazepine 31
• cisapride 32 , 33 , 34
• clomipramine 35
• cyclosporine 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48
• dextromethorphan 49
• diltiazem 50
• erythromycin 51
• estrone 52
• ethinyl estradiol 53
• felodipine 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63
• fluvoxamine 64
• losartan 65
• lovastatin 66 , 67
• midazolam 68 , 69
• nicardipine 70
• nifedipine 71
• nimodipine
• nisoldipine 71 , 72 , 73
• pimozide 74
• praziquantel 75
• saquinavir 76 , 77
• scopolamine 78
• simvastatin 79 , 80
• triazolam 81 , 82 , 83 , 24
• verapamil 84 , 85

Drug plasma concentrations decreased by grapefruit juice, resulting from decreased absorption: Fexofenadine, 86 , 87 , 88 , 89 itraconazole. 90 , 91

Drugs with increased time to reach peak concentrations due to grapefruit juice ingestion: Clarithromycin. 92

Drugs with delayed absorption and time to reach peak concentrations due to grapefruit juice ingestion: Indinavir, 93 , 94 , 95 quinidine. 96 , 97

Drug plasma concentrations slightly increased by grapefruit juice, mechanism unknown: Digoxin, 98 sildenafil. 99 , 100

Drug plasma concentrations decreased by grapefruit juice, mechanism unknown: Amprenavir, 101 etoposide. 102

Drugs that do not appear to interact with grapefruit juice based on available documentation: Alprazolam. 103

Other reports are available regarding the effect of grapefruit juice on caffeine metabolism, 104 inhibition of 11-beta-hydroxysteroid dehydrogenase 105 and shifting the metabolic ratios of clomipramine. 35

Adverse Reactions

Grapefruit juice has been associated with hypotension in one patient. 106

Toxicology

Grapefruit juice can create adverse effects by altering drugs metabolized by the CYP3A4 enzyme system (eg, some nonsedating antihistamines, benzodiazepines, selected calcium channel blockers, estrogens, quinidine, and cyclosporine).

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