Grapefruit affects a great number of drugs, including drugs for heart disorders and cholesterol-lowering drugs. Read on to learn about why and how grapefruit messes with your drugs, and what are the risks and side effects of these interactions.
- Key Points about Grapefruit and Your Medications
- Scientific Research on Grapefruit
- Why Is Grapefruit-Drug Interaction still a Problem?
- Who is at Higher Risk of Grapefruit-Drug Interactions?
- Drugs that Interact with Grapefruit
- Risks and Side Effects
Key Points about Grapefruit and Your Medications
- More than 85 drugs have the possibility of interacting with grapefruit. Over 40 of these can cause serious effects [R].
- Drugs that react with grapefruit are all taken by mouth and require a relatively low dose to have an effect [R].
- Grapefruit juice can increase the blood concentration of some drugs and decrease the concentration of others, causing either more severe reactions or a lack of effectiveness, respectively [R].
- Of most concern is grapefruit’s effect on calcium channel blocker heart drugs and the statin group of drugs, used in the treatment of heart disease [R].
- Reacting drugs should not be consumed with grapefruit or its products, or alternative non-interacting medications should be prescribed [R].
- Older patients are more likely to consume both grapefruit and interacting medications and are at highest risk of negative effects [R].
- Your genes can determine how you react to grapefruit, you should always take care to not harm yourself and SelfDecode can help you understand your genes and substance interactions better.
Scientific Research on Grapefruit
In the early 1990s, investigators found that grapefruit juice could markedly increase the levels and action of drugs taken orally. This was an unexpected observation in a study of felodipine, a calcium channel blocker used to treat high blood pressure [R].
This discovery led to further investigations of grapefruit’s constituents, drug interactions, and the mechanisms involved [R].
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 [R].
However, some investigators believe that only a few drugs product significant reactions (these include simvastatin, buspirone, felodipine, and possibly cyclosporine). This is because many studies involve exposure quantities of grapefruit juice far higher than that normally consumed [R].
They claim that the risk of grapefruit interactions with many other drugs, including quinine, quinidine, erythromycin, dextromethorphan, oxycodone, tolvaptan, nilotinib, and sunitinib, are clinically unimportant [R, R].
Mechanisms of the Grapefruit Effect
Why Does Grapefruit Mess with Your Medicine?
Grapefruit increases the effect of some drugs and decreases the absorption of others.
There are 3 main ways in which grapefruit interacts with drugs; however, these can also be modified by genetics, and vary individually [R].
Furanocoumarins found in grapefruit (mainly 6’7′-dihydroxybergamottin) 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 [R].
This can result in:
- Stronger effects with the same dose, due to the higher blood levels of the drug. Also, more side effects.
- Weaker effects with the same dose. This would happen when the drug you take actually needs CYP3A4 to transform it into the active compound (e.g. amiodarone, clopidogrel).
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 (drugs and toxins).
This would increase the amount of the drug that makes it into the bloodstream.
In addition, the interaction is more complex, because these effects can be offset/augmented by grapefruit also blocking the CYP3A enzymes [R].
OATPs (organic anion transporting polypeptides) are cell transporters involved in the transport of a number of widely used drugs.
Grapefruit Compounds Responsible for these Effects
The compounds thought to be responsible for interfering with drugs include [R]:
- Flavonoid glycosides (narirutin, naringin, naringenin, quercetin, kaemferol, hesperidin, neohesperidin, didymin, and poncirin)
- Furanocoumarins (6′,7′-dihydroxybergamottin, bergamottin)
- Sesquiterpens (nootkatone).
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 separating (taking the drug and grapefruit at different times) [R].
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 not reported [R, R].
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 grapefruit juice that doesn’t interact with drugs – “interaction-free.” The question is whether this juice would provide the same health benefits as the unprocessed one [R].
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 [R]
- Only a low the fraction of the drug reaches the blood [R]
- They are metabolized by CYP3A4 (or transported by OATP, Pgp) [R]
Knowledge of the chemical pathways taken by a particular drug in the body help predict a clinical interaction [R].
What Determines the Magnitude of the Interaction?
- The seriousness of the dose-related drug toxicity (and side effects) [R]
- The extent to which the drug concentration increases in the blood [R]
- The fraction of the drug that normally enters the blood [R]
- The timing and type of grapefruit product taken (whole, juice, seed extract) [R]
- Individual risk differences (age, ethnicity, genetics) [R]
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 [R].
Why Is Grapefruit-Drug Interaction still a Problem?
There is a lack of knowledge about the grapefruit reaction in the general health care community. Unless health professionals are aware of a 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 [R].
Current data does not provide an absolute or even approximate number of the true incidence of grapefruit-drug interactions [R].
Who is at Higher Risk of Grapefruit-Drug Interactions?
Older people are especially at risk for grapefruit-drug interactions because:
- A large proportion of the population, people older than 45 years are the prime purchasers of grapefruit. They also receive the most prescriptions for drugs [R, R]
- They are more likely to be taking medication for degenerative disorders [R]
- Older adults are less able to tolerate excessive drug levels in the blood [R]
Also, reported ethnic differences in the activity of this enzyme may be partly due to dietary factors [R].
Medications taken by mouth are most affected, as the enzyme/drug interaction occurs in the intestines, rather than the liver. The same drug may be well tolerated if given intravenously [R].
Drugs that Interact with Grapefruit
A list of drugs that interact with grapefruit is available. This list is based on data from 2012 through 2013. Many new drugs not listed will also produce a similar risk. Also, drugs have different trade names in different countries [R, R].
The frequency of serious grapefruit-drug interactions is likely underreported [R].
Grapefruit DECREASES the Effects of These 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 stops this action [R, R].
- Ciprofloxacin (Cipro, Cipro XR). Orange juice decreases the levels of this drug, and grapefruit juice may have a similar effect [R].
- 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 [R, R].
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 [R, R].
- Prasugrel (Effient) [R].
- Acebutolol (Sectral, Prent). Due to OATP1A2 inhibition [R].
- Atenolol (Tenormin). Due to OATP1A2 inhibition [R].
- Sotalol (Betapace). Due to OATP1A2 inhibition [R].
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 [R, R]. This is the case of young girls who are both on birth control and using grapefruit for weight loss.
- Methotrexate (MTX) is primarily eliminated through the kidneys unchanged so would likely undergo a significant reduction in blood levels when taken by mouth with grapefruit [R].
- Etoposide (Toposar, VePesid, Etopophos). Blood levels may reduce by 50% when taken with grapefruit [R].
Nonsteroidal Anti-inflammatory Drugs
Grapefruit INCREASES the Effects of These Drugs
Antihypertensives (meds for high blood pressure)
- 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 [R, R].
- Nifedipine (Adalat, Procardia) [R].
- Nitrendipine. In most people tested, there was a small temporary increase in heart rate after taking nitrendipine with grapefruit [R].
- Nisoldipine (Sular). Grapefruit juice increased the maximum concentration of nisoldipine and reduced the time to reach maximum concentration [R].
- Diltiazem (Cardizem). Blood levels of this drug rise when taken with grapefruit juice. Inhibition of intestinal metabolism and/or P-glycoprotein out flow 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 [R, R].
- Verapamil (Calan). There are conflicting reports about the interaction of verapamil with grapefruit juice. One study showed an increase in its blood level at steady state, while another showed no significant change after a single dose [R].
- Losartan (Cozaar) – May interact [R].
- Valsartan (Diovan) – May interact [R].
- Sunitinib (Sutent). Grapefruit causes a small increase in exposure that may not be clinically relevant [R].
- Dasatinib (Sprycel) [R].
- Erlotinib (Tarceva) [R].
- Nilotinib (Tasigna). Grapefruit increases drug levels by up to 60% [R].
Antiplatelet Drugs (against blood clots)
- Erythromycin (antibiotic) Interaction may not be clinically important [R].
- Saquinavir (Invirase, Fortovase). Grapefruit juice dose-dependently increases blood levels of this anti-AIDS drug [R].
- Artemether (antimalarial) [R, R].
- Halofantrine (antimalarial) [R].
- Primaquine (antimalarial) [R].
- Quinine (antimalarial). Grapefruit juice reduces quinine removal from the blood [R].
- Albendazole (antiparasitic) shows an increase in blood levels with grapefruit juice [R].
- 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 [R].
Benzodiazepines and CNS Drugs
- Midazolam (Versed). Grapefruit juice increases drug levels. This is particularly important when other factors also 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 [R, R, R].
- Triazolam (Halcion). Similar results have also been seen with triazolam [R].
- Carbamazepine (Tegretol). Grapefruit juice increases the blood levels of the anticonvulsant carbamazepine [R, R].
- Buspirone (Buspar). Grapefruit juice considerably increases blood concentrations of buspirone [R].
- Sertraline (Zoloft). Grapefruit juice considerably increases blood concentrations of sertraline [R].
- Dextromethorphan [R, R]. The interaction may not be clinically important.
- Ketamine (Ketalar) [R].
- Methadone (Dolophine). Grapefruit juice modestly increases methadone levels [R].
- Oxycodone [R]. The interaction may not be clinically important.
- Fentanyl [R].
- Morphine [R].
- 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 [R, R, R].
- Domperidone (Motilium) [R].
Statins and other Cholesterol-lowering Drugs
- Simvastatin (Zocor). Simvastatin is particularly sensitive to the grapefruit effect, 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 on the concentration of is only about 10% of the effect observed when grapefruit juice and simvastatin are taken at the same time. [R, R].
- Lovastatin (Mevacor). Lovastatin can be also 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 [R, R].
- Atorvastatin (Lipitor). Atorvastatin is less affected if it is taken in the evening and grapefruit juice is ingested in the morning, as the drug levels do not rise as much and muscle tissue is not affected. Staggering the ingestion of atorvastatin and grapefruit may reduce risk [R, R].
- 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. [R, R, R, R].
- 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 [R, R].
- Sirolimus (Rapamycin) [R].
- Metformin (Glucophage). Although grapefruit juice may benefit diabetic patients, it may worsen lactic acidosis in diabetic patients taking metformin [R].
- Repaglinide (Prandin). Grapefruit juice interacting with the antidiabetic agent repaglinide may cause low blood sugar levels [R].
Nonsteroidal Anti-inflammatory Drugs
- Diclofenac (Voltaren, Cataflam). Double strength grapefruit juice increases the anti-inflammatory effect of diclofenac in rats [R].
Urinary Tract Agents
- Darifenacin (Enablex). This medication for overactive bladder syndrome is broken down by liver CYP3A enzymes. It has a moderate to intermediate potential of interacting with grapefruit [R, R].
- Oxybutynin (Ditropan) [R, R].
- Solifenacin (Vesicare) [R, R].
- Silodosin (Rapaflo) [R].
- Tamsulosin (Alna, Flomax) [R].
- 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 the dangerous heart arrhythmia called Torsade-des-pointes. This drug is used no longer due to this effect when taken with grapefruit and many other drugs [R, R, R, R].
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 age of the person and their level of kidney function [R, R]. Interaction with grapefruit may cause serious generalized vasodilatation.
- Tadalafil (Cialis). Interaction with grapefruit may cause serious generalized vasodilatation [R, R].
- Vardenafil (Levitra). May cause serious generalised vasodilatation [R].
- 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 [R].
- Colchicine [R].
- 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 [R].
Risks and Side Effects
Grapefruit comes in many varieties with different levels of active components depending on the variety, maturity, origin of the fruit, local climatic conditions, and the manufacturing process. No single component accounts for all observed interactions [R].
The risks of taking grapefruit products with certain drugs include:
- Drug overdose [R]
- Dose-dependent negative side effects [R]
- Serious conditions such as rapid irregular heartbeat, muscle breakdown, bone marrow suppression (this causes decreased blood cell production), breathing difficulties, gut bleeding, kidney toxicity [R]
- Death due to organ failure, stroke, or gangrene [R]
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 heart beat are 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 heartbeat [R, R, R].
Rhabdomyolysis occurs when the concentration of a drug 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 [R].
Rhabdomyolysis has been reported with grapefruit ingested in usual amounts. This dangerous condition can occur even with the ingestion of much less grapefruit than was previously expressed by the US Food and Drug Administration [R, R, R].
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 (i.e., 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 [R, R].
A large study of 50 000 women showed an increased risk of developing breast cancer when estrogens were taken with grapefruit juice [R].
However, a follow-up study with 114,504 women found no such association. They adjusted their result for reproductive history, body mass index, energy intake, and alcohol intake [R].
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