Why Grapefruit Affects Your Medication

Grapefruit affects a great number of over-the-counter and prescription drugs. Read on to learn about why and how grapefruit messes with your medications, and what are the risks and side effects of these interactions.

Scientific Research on Grapefruit

In the early 1990s, scientists found that grapefruit juice could markedly increase the levels and action of drugs taken orally. This discovery led to further investigations of grapefruit’s constituents, drug interactions, and the mechanisms involved [1, 2].

Drugs that interact with one or more of grapefruit’s many biologically active substances are increasingly available. Many are frequently prescribed and essential for treating common medical conditions [3].

Of concern is that new drugs tend to be released before grapefruit interaction testing, putting patients at risk [4, 5, 6].

However, some scientists believe that only a few drugs can produce significant reactions (these include simvastatin, buspirone, felodipine, and possibly cyclosporine). This is because many of the interaction studies involve exposure to quantities of grapefruit juice far higher than that normally consumed [7].

They claim that the risk of grapefruit interactions with many other drugs, including quinine, quinidine, erythromycin, dextromethorphan, oxycodone, tolvaptan, nilotinib, and sunitinib, are clinically not relevant [8, 9].

Mechanisms of the “Grapefruit Effect”

Why and How Grapefruit Messes with Your Medications

There are 3 main ways in which grapefruit interacts with drugs; however, these can also be modified by genetics, and vary from person to person [10].

1) CYP3A4 Inhibition

Furanocoumarins found in grapefruit block the CYP3A4 enzyme. This is an enzyme found in the small intestine and the liver that breaks down (metabolizes) drugs. It is responsible for processing about 50% of all prescribed drugs [11].

When grapefruit juice is consumed, CYP3A4‘s ability to break down the drug is decreased [12, 13].

This can result in:

• Stronger effects, due to higher blood levels of the drug. Also, more side effects.
• Weaker effects. This would happen when the drug you take actually needs CYP3A4 to transform it into the active compound (e.g. amiodarone, clopidogrel).

Apart from CYP3A4, grapefruit components can also block CYP1A2, CYP2A6, CYP2C9, CYP2C19, and CYP2D6 [14].

Scientists think that grapefruit also likely blocks CYP3A5 with the same intensity as CYP3A4 (these enzymes have highly similar functions), but this hasn’t been properly studied [15].

2) P-glycoprotein Pump Inhibition/Activation

P-glycoprotein pump or Pgp (MDR1, ABCB1) is found in the gut lining, where it pumps drugs back into the gut. It is also found in the liver, kidneys, blood-brain and blood-testis barrier. It has an important function in protecting our body from foreign chemicals, such as drugs and toxins.

Several studies suggest that grapefruit blocks the pump by both decreasing its production and blocking its function. This would increase the amount of the drug that makes it into the bloodstream and enhance the effect drugs can have on the body [16, 17].

However, other studies suggest that grapefruit juice may also activate the pump, which would mean a greater flow of the drug back into the gut and away from the blood [2, 18].

In addition, the interaction is more complex, because these effects can be offset/augmented by grapefruit also blocking the CYP3A enzymes [18].

So, it is not completely understood how grapefruit juice affects transport across the pump. In addition, a scientific review on the topic suggests that grapefruit might have a “minimal” effect on drug absorption in the body [7].

3) OATP Inhibition

OATPs (organic anion transporting polypeptides) are cell transporters involved in the transport of a number of widely used drugs.

Grapefruit may block OATPs (including OATP1A2, OATP1B1, and OATP2B1), and thereby decrease the transport of the drug from the gut into the bloodstream. This decreases drug availability [19, 7].

Grapefruit Compounds Responsible for these Effects

Grapefruit comes in many varieties with different levels of active components depending on the variety, maturity, origin of the fruit, local climate conditions, and the manufacturing process. No single component accounts for all observed interactions [20].

The compounds thought to be responsible for interfering with drugs include [2]:

• Flavonoid glycosides (narirutin, naringin, naringenin, quercetin, kaempferol, hesperidin, neohesperidin, didymin, and poncirin)
• Furanocoumarins (6′,7′-dihydroxybergamottin, bergamottin)
• Sesquiterpenes (nootkatone)

Several studies have shown DHB (6′,7′-dihydroxybergamottin) and to an extent, bergamottin to be important contributors to the grapefruit juice effect (blocking CYP3A enzymes) [21, 22, 23].

On the other hand, the flavonoids, especially naringin, are the grapefruit constituents responsible for clinically significant OATP inhibition. In contrast to CYP3A, OATP inhibition is short-lived, and the reaction can be avoided by taking the drug and grapefruit at different times [7].

The complex chemistry of grapefruit juice makes its use in drug interaction studies challenging. The concentrations of bergamottin, DHB, and naringin that produce adverse effects are often not reported [7, 24].

There is some effort to produce grapefruit juice without furanocoumarins by removing these via methods such as filtration, heating, or UV exposure. This would potentially create “interaction-free” grapefruit juice that doesn’t interact with drugs. The question, however, is whether this juice would provide the same health benefits as the unprocessed one [7].

What Determines Which Drugs Are Affected?

The interaction between medications and grapefruit is drug-specific. Each drug is broken down and passes through the body in different ways.

Affected drugs possess 3 essential characteristics:

• They are taken by mouth. Enzyme/drug interaction occurs mostly in the intestines, rather than the liver. The same drug may be well tolerated if given intravenously [3, 2].
• Only a low fraction of the drug reaches the blood [3]
• They are metabolized by CYP3A4 (or transported by OATP or Pgp) [3]

What Determines the Magnitude of the Interaction?

• The seriousness of the dose-related drug toxicity (and side effects) [3]
• The extent to which the drug concentration increases in the blood [3]
• The timing and type of grapefruit product taken (whole, juice, seed extract) [3]
• Age, ethnicity, and genetics [3]

Generally speaking, a grapefruit-drug interaction is likely to be of clinical importance if the drug has a narrow therapeutic range, or when the drug’s movement through the body is dramatically altered by grapefruit [7].

Why Is Grapefruit-Drug Interaction still a Problem?

Unless health professionals are aware of the recent addition of grapefruit to a patient’s diet, they may not investigate grapefruit as a cause of a negative drug reaction. Also, patients may not volunteer this information and many of them don’t realize it is of importance [3].

That is why some scientists think that current data does not provide an absolute or even approximate number of the true incidence of grapefruit-drug interactions [3].

Who is at Higher Risk of Grapefruit-Drug Interactions?

Older people are especially at risk for grapefruit-drug interactions because [25, 26, 27]:

• People older than 45 years are the prime purchasers of grapefruit
• They also receive the most drug prescriptions
• Older adults are less able to tolerate excessive drug levels in the blood

Also at risk are people with certain genetic differences that impact the production of the enzymes CYP3A4/CYP3A5 [2, 28, 15].

Drugs that Interact with Grapefruit

Below is a list of drugs that interact with grapefruit, based on data gathered from 2012 through 2013. Many new drugs not listed will also produce a similar risk. Also, drugs have different trade names in different countries [29, 3].

Grapefruit DECREASES the Effects of These Drugs

Antiarrhythmic drugs

• Amiodarone (Cordarone, Nextrone). When amiodarone is broken down by CYP3A the product, N-desethylamiodarone (N-DEA), is stronger than the original drug. Grapefruit juice almost completely blocks this conversion [30, 31].

Antibiotics

• Ciprofloxacin (Cipro, Cipro XR). Orange juice decreases the levels of this drug, and grapefruit juice may have a similar effect [32].

Antihistamines

• Fexofenadine (Allegra). This non-drowsy antihistamine can interact not only with grapefruit juice but also with apples and orange juice. Blood levels of the drug go down (due to OATP inhibition) and the effectiveness may be reduced. A study of healthy adults shows that the absorption of fexofenadine is reduced by 30% when taken with grapefruit juice [13, 33].

Antiplatelet Drugs (Against Blood Clots)

• Clopidogrel (Plavix). Grapefruit juice decreases drug levels and can markedly decrease the platelet-inhibitory effect of clopidogrel in human volunteers [34, 35].
• Prasugrel (Effient) [36].

Beta Blockers

• Acebutolol (Sectral, Prent). Due to OATP1A2 inhibition [37].
• Atenolol (Tenormin). Due to OATP1A2 inhibition [37].
• Sotalol (Betapace). Due to OATP1A2 inhibition [37].

Birth Control Pills

• Oral contraceptives. Grapefruit may decrease the breakdown of estrogens. In a randomized crossover study of 13 healthy volunteers, grapefruit juice increased the fraction of estrogen that reached the blood. It’s not known if this can make the pill less effective [38, 39]. This is the case of young girls who are both on birth control and using grapefruit for weight loss.

Chemotherapy Drugs

• Methotrexate (MTX) [40].
• Etoposide (Toposar, VePesid, Etopophos). Blood levels may reduce by 50% when taken with grapefruit [41].

Nonsteroidal Anti-inflammatory Drugs

• Acetaminophen (Paracetamol, Tylenol) [42].

Thyroid Hormones

• L-thyroxine (Levoxyl) [43].

Grapefruit INCREASES the Effects of These Drugs

Antihypertensives (Blood Pressure Meds) and Antiarrhythmic Drugs

• Felodipine (Plendil). The interaction between grapefruit and felodipine increases with increasing frequency and amount of grapefruit juice taken. An interval of 2 to 3 days between grapefruit juice and felodipine administration is necessary if the interaction is to be avoided [44, 27].
• Nifedipine (Adalat, Procardia) [45].
• Nitrendipine. In most people tested, there was a small temporary increase in heart rate after taking nitrendipine with grapefruit [46].
• Nisoldipine (Sular). Grapefruit juice increased the maximum concentration of nisoldipine and reduced the time to reach maximum concentration [47].
• Diltiazem (Cardizem). Blood levels of this drug rise when taken with grapefruit juice. Inhibition of intestinal metabolism and/or P-glycoprotein outflow transport may be responsible for this effect. However, another study showed blood levels to be unchanged with grapefruit juice suggesting that other factors may be contributing [48, 49].
• Verapamil (Calan). There are conflicting reports about the interaction of verapamil with grapefruit juice. One study showed an increase in its blood level at a steady state, while another showed no significant change after a single dose [50].
• Losartan (Cozaar) – May interact [51].
• Valsartan (Diovan) – May interact [51].

Anticancer Drugs

• Sunitinib (Sutent). Grapefruit causes a small increase in exposure that may not be clinically relevant [52].
• Dasatinib (Sprycel) [53].
• Erlotinib (Tarceva) [54].
• Nilotinib (Tasigna). Grapefruit increases drug levels by up to 60% [55].

Antiplatelet Drugs (Against Blood Clots)

• Ticagrelor (Brilinta) [56].

Antibiotics, Antivirals, and Antiparasitic Drugs

• Erythromycin (antibiotic) Interaction may not be clinically important [57].
• Saquinavir (Invirase, Fortovase). Grapefruit juice dose-dependently increases blood levels of this anti-AIDS drug [58].
• Artemether (antimalarial) [59, 60].
• Halofantrine (antimalarial) [61].
• Primaquine (antimalarial) [62].
• Quinine (antimalarial). Grapefruit juice reduces quinine removal from the blood [63].
• Albendazole (antiparasitic) shows an increase in blood levels with grapefruit juice [64].
• Praziquantel (Biltricide). Grapefruit juice significantly increases the levels of this antiparasitic in the blood and may also be used to increase the effectiveness of the drugs without harm [65].

Benzodiazepines and CNS Drugs

• Midazolam (Versed). Grapefruit juice increases drug levels. This is particularly important when other factors also increase them, such as advanced age, cirrhosis of the liver, and taking other drugs affecting the CYP450 system. Dentists frequently use midazolam as a sedative in children. If the injectable form is given orally, its bitter taste may be hidden using grapefruit juice. This results in increased blood levels of midazolam, causing excessive levels of sedation [66, 67, 68].
• Triazolam (Halcion). Similar results have also been seen with triazolam [69].
• Carbamazepine (Tegretol). Grapefruit juice increases blood levels [70, 71].
• Buspirone (Buspar). Grapefruit juice increases blood levels [72].
• Sertraline (Zoloft). Grapefruit juice increases blood levels [73].
• Dextromethorphan [74, 75]. The interaction may not be clinically important.
• Ketamine (Ketalar) [76].

Opioids

• Methadone (Dolophine). Grapefruit juice modestly increases methadone levels [77].
• Oxycodone [78]. The interaction may not be clinically important.
• Fentanyl [79].
• Morphine [80].

Gastrointestinal Agents

• Cisapride (Propulsid). Studies show that a single glass of grapefruit juice produced an individually variable increase in the blood levels of cisapride by blocking the intestinal cytochrome P450 3A4 (CYP3A4) activity and may cause heart arrhythmia [81, 82, 83].
• Domperidone (Motilium) [84].

Statins and other Cholesterol-lowering Drugs

• Simvastatin (Zocor). Simvastatin is particularly sensitive to grapefruit, showing excessively high drug levels when taken with whole grapefruit and grapefruit juice. When simvastatin is taken 24 hours after taking a “high dose” of grapefruit juice, the effect is only about 10% of the effect observed when grapefruit juice and simvastatin are taken at the same time [85, 86].
• Lovastatin (Mevacor). Lovastatin can also be dangerously increased by grapefruit.
  However, a glass of regular-strength grapefruit juice has a minimal effect on the blood concentration after a 40 mg evening dose of lovastatin [87, 88].
• Atorvastatin (Lipitor). Atorvastatin is less affected if it’s taken in the evening and grapefruit juice is ingested in the morning, as the drug levels do not rise as much [89, 90].

Immunosuppressant Drugs

• Cyclosporine (Neoral, Sandimmune). When cyclosporine is taken with grapefruit juice compared with water, there is a significant increase in the blood level, likely due to p-glycoprotein inhibition [91, 92, 93, 94].
• Tacrolimus (Prograf, Advagraf, Protopic). Levels can increase up to 1000% after ingesting grapefruit juice (250 mL, 4 times/d for 3 d). There is a case where levels increased by 500% after consuming grapefruit marmalade for one week, resulting in acute kidney failure [95, 96].
• Sirolimus (Rapamycin) [97].

Anti-Diabetic Drugs

• Metformin (Glucophage). Although grapefruit juice may benefit diabetic patients, it may worsen lactic acidosis in diabetic patients taking metformin [98].
• Repaglinide (Prandin). Grapefruit juice interacting with the antidiabetic agent repaglinide may cause low blood sugar levels [51].

Nonsteroidal Anti-inflammatory Drugs

• Diclofenac (Voltaren, Cataflam). Double strength grapefruit juice increases the anti-inflammatory effect of diclofenac in rats [99]. Effects in humans unknown.

Urinary Tract Agents

• Darifenacin (Enablex). This medication for overactive bladder syndrome is broken down by liver CYP3A enzymes. It has a moderate to an intermediate potential of interacting with grapefruit [100, 101].
• Oxybutynin (Ditropan) [100, 101].
• Solifenacin (Vesicare) [100, 101].
• Silodosin (Rapaflo) [102].
• Tamsulosin (Alna, Flomax) [102].

Antihistamines

• Terfenadine (Seldane) is nearly completely removed after the first pass by CYP3A4, so grapefruit raises blood levels of this drug. High blood levels of terfenadine may cause a dangerous heart arrhythmia called Torsade-des-pointes. This drug is used no longer due to this side effect [103, 104, 105, 2].

Erectile Dysfunction Medication

• Sildenafil (Viagra). When taken by mouth, it is rapidly absorbed but reduced in effectiveness by 60% due to the enzymatic action of the CYP enzymes. This effect is variable according to the age of the person and their kidney function [106, 107]. Interaction with grapefruit may cause serious generalized vasodilatation (blood vessel expansion).
• Tadalafil (Cialis). Interaction with grapefruit may cause serious generalized vasodilatation [51, 108].
• Vardenafil (Levitra). May cause serious generalised vasodilatation [51].

Other Interactions

• Nicotine is processed by the enzyme CYP2A6, which grapefruit inhibits. Large doses of grapefruit can delay the time to peak concentration, although clearance through the kidneys is enhanced [14].
• Colchicine [109].
• Xanthines found in coffee and teas are also processed by grapefruit-affected enzymes. While there may be a reduction in the absorption of theophylline in teas, it does not increase the effect of caffeine [110].

Risks and Side Effects

The risks of taking grapefruit products with certain drugs include:

• Drug overdose [20]
• Dose-dependent negative side effects [20]
• Serious conditions such as rapid irregular heartbeat, muscle breakdown, bone marrow suppression (this causes decreased blood cell production), breathing difficulties, gut bleeding, kidney toxicity [3]
• Death due to organ failure, stroke, or gangrene [51]

Examples of Severe Grapefruit-Drug Interactions

Torsade de Pointes

Torsade de pointes is a particular type of abnormally fast heart rhythm, with the risk of sudden death. It occurs when the measured interval between two parts of the heartbeat is excessively prolonged. The effect of the antiarrhythmic drug amiodarone and its active chemical dronedarone, when taken with grapefruit juice, is significantly increased compared to when taken with water. This can lead to dangerous variations in the heartbeat [31, 111, 3].

Torsade de pointes can also occur with certain anticancer drugs, such as nilotinib and sunitinib [55, 52].

Rhabdomyolysis

Rhabdomyolysis occurs when the concentration of some drugs becomes too high. The drug-induced toxicity damages muscles, causing the release of large quantities of muscle proteins into the blood and acute kidney failure. Statins can produce this effect at high concentrations [112].

Rhabdomyolysis has been reported with grapefruit ingested in usual amount [113, 114, 85].

Nephrotoxicity (Kidney Damage)

Nephrotoxicity is damage to the kidneys caused by drugs. It can occur with high levels of drugs that prevent organ rejection after transplant (cyclosporine and tacrolimus). Both of these drugs have a narrow beneficial range below which they lack sufficient effect and above which they cause toxicity. Concentrations of these drugs can increase by up to 600% when taken with grapefruit [115, 3].

Breast Cancer?

Studies disagree over the risk of breast cancer in postmenopausal women taking estrogen therapy and consuming grapefruit [3, 39].

A large study of 50,000 women showed an increased risk of developing breast cancer when estrogens were taken with grapefruit juice [116].

However, a follow-up study with over 114,500 women found no such association. They adjusted their results for reproductive history, body mass index, energy intake, and alcohol intake [117].