Interactions of grapefruit juice and cardiovascular medications: A potential risk of toxicity

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Does grapefruit affect my medicine?

Eating grapefruit or drinking grapefruit juice can affect some medicines. In most cases, it increases the level of the medicine in your blood. This can increase the risk of side effects or alter the effect the medicine has.

If your usual diet includes grapefruit or grapefruit juice and you’ve been prescribed a medicine that’s affected by grapefruit, speak to your GP or pharmacist. Do not stop taking your medicine without advice.

Medicines affected by grapefruit

Statins

Statins are medicines that lower your cholesterol. Grapefruit or grapefruit juice affects some statins.

Do not drink grapefruit juice if you’re taking simvastatin. Grapefruit juice increases the level of simvastatin in your blood and makes side effects more likely.

Atorvastatin interacts with grapefruit juice if you drink large quantities (more than 1.2 litres daily), but an occasional glass is thought to be safe.

Currently, healthcare professionals advise it is safe to drink grapefruit juice and eat grapefruit if you’re taking other types of statins.

Calcium channel blockers

Calcium channel blockers are medicines that relax the muscles that make up the walls of your arteries. They’re used as part of the treatment of conditions such as high blood pressure (hypertension) and coronary heart disease.

Grapefruit juice interacts with some calcium channel blockers and increases the level of the medicine in your blood. If you’re taking any of the medicines below, seek advice from your pharmacist or doctor if you wish to include grapefruit or grapefruit juice in your diet.

• amlodipine
• felodipine
• lacidipine
• lercanidipine
• nicardipine
• nifedipine
• nimodipine
• verapamil

Grapefruit juice does not affect diltiazem.

Anticoagulants

Anticoagulants are medicines that help to prevent blood clots. They’re given to people at high risk of getting clots, to reduce their chances of serious conditions such as strokes and heart attacks.

Do not drink grapefruit juice if you’re taking warfarin. It can increase the effect of warfarin on your blood, making you bleed more easily.

It’s safer to drink grapefruit juice if you’re taking the newer anticoagulants rivaroxaban, dabigatran, apixaban or edoxaban.

Antiplatelet medicines

Antiplatelet medicines prevent platelets (a type of blood cell) from sticking together and forming blood clots. They help to prevent heart attacks and strokes.

Do not drink grapefruit juice if you’re taking the antiplatelet medicine clopidogrel, as it may mean your medicine works less effectively.

If you’re taking ticagrelor, grapefruit may increase the effects of your medicine and make you bleed more easily.

You do not need to avoid grapefruit if you’re taking dipyridamole or low-dose aspirin.

Ciclosporin and immunosuppressants

Ciclosporin, sirolimus and tacrolimus are medicines that moderate your immune system (the body’s natural defence system).

If you’re taking any of these medicines, do not drink grapefruit juice without consulting your doctor.

Entocort

Entocort is a medicine that contains budesonide and is used to treat Crohn’s disease, a condition that affects the digestive system.

Do not eat grapefruit or drink grapefruit juice while you’re taking this medicine, as the level of budesonide in your blood will increase.

Cytotoxic medicines

Some medicines used in the treatment of cancers may interact with grapefruit juice. You should check with your doctor before drinking grapefruit juice.

Other medicines

This list is not exhaustive and there are a number of other drugs that may interact with grapefruit. The risk of experiencing the effect of a drug interaction as a result of grapefruit can vary a lot from person to person.

For more information check the patient information leaflet that comes with your medicine, or you can ask your pharmacist or GP or call NHS 111 for advice.

Read the answers to more questions about medicines.

Further information

• Why must some medicines be taken with or after food?
• Why must some medicines be taken on an empty stomach?
• Coronary heart disease
• High blood pressure
• Statins

Page last reviewed: 14 September 2021
Next review due: 14 September 2024

Portfolio – 2015

1. Main
2. Translations
3. Translation portfolio
4. 2015

In 2015, we transferred registration dossiers, modules and medical articles for the following drugs and substances:

• Taxol
• Vizin
• Magnetrans Active
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• Fenspiride
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• Pentoxifylline
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• Le Petite Marseille
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• Mirvedol
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• Magnetrans Active
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• Mepakt
• Calcium-D3 Nycomed
• Marcain
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• Gaviscon
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• Keto analogues of amino acids
• Dolenio
• Atakand Plus
• Donasert
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• Phosphocreatine
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• Le Petit Marseillais Shower gel for men Juniper and fern extract
• Le Petit Marseillais Shower Gel Intense Nourishing Olive Oil, Beeswax & Sweet Almond
• Le Petit Marseillais Shower Cream Intense Moisturizing Cocoa & Sesame
• Le Petit Marseillais Shower Gel Apricot & Hazelnut
• Le Petit Marseillais Orange Tree & Argan Gel Shampoo for Men
• Le Petit Marseillais Shower Gel Mint
• Le Petit Marseillais Colored Hair Conditioner Pomegranate & Argan Oil
• Le Petit Marseillais Conditioner for damaged hair Shea butter and Argan
• Le Petit Marseillais Conditioner for Fine Hair Nourishment and Shine Tricolor Extract and Almond Milk
• Le Petit Marseillais Mask for damaged hair Shea butter and Argan
• Le Petit Marseillais Shampoo for Colored Hair Pomegranate and Argan Oil
• Le Petit Marseillais Shampoo for damaged hair Shea Butter and Argan
• Le Petit Marseillais Shampoo for Fine Hair Volume and Shine Tricolor Extract and Grapefruit
• Analgin
• Movalis, ampoules
• Lazivir

and other drugs.

Grapefruit drug interactions | Ukrainian Medical Chronicle

Abstract

This mini-review discusses the main scientific concepts and clinical manifestations of grapefruit drug interactions. Grapefruit and, to a lesser extent, bitter oranges, pomeloes, and limes can interact with certain oral medications. Furanocoumarins appear to be the main active ingredient. Oranges of sweet varieties of furanocoumarins do not contain. The interaction is based on the inactivation of the CYP 3A4 enzyme, which is involved in the metabolism of many drugs. Some clinically significant side effects are discussed. Drug interactions with grapefruit are generally regarded as undesirable, but grapefruit’s bioavailability-enhancing properties may be of practical use to reduce drug doses. The pharmacological action of grapefruit is subject to significant fluctuations, which is associated with dosage difficulties in a narrow therapeutic window. In this regard, it seems promising to develop drugs based on grapefruit components that could be dosed more accurately. Thus, grapefruit, like other citrus fruits, is a valuable food product. However, its interactions with certain drugs can lead to overdose symptoms. Understanding these mechanisms is important for determining indications and contraindications for the use of grapefruit in combination with various drugs.

Recently, the effect of grapefruit on the effectiveness of certain drugs has been repeatedly reported (Kanazawa S. et al., 2001; Mahgoub A.A., 2002; Okura T. et al., 2008; Seidegård J. et al., 2009; Nieminen T.H. et al. , 2010; Bailey D.G. et al., 2013). Other citrus fruits have a similar property to some extent: bitter oranges (Seville), pomelo and lime (Malhotra S. et al., 2001; Guo L.Q. et al., 2007). Drug interactions with sweet oranges (Neville, Valencia) have not been reported (Bailey D.G. et al., 2013). The effect of grapefruit varieties (white, pink) and storage conditions has not been studied enough.

The main mechanism of interaction between grapefruit and drugs is the inactivation of enzymes of the cytochrome P450 family, especially CYP 3A4, which is involved in the metabolism of many drugs. The enzyme is localized in the epithelium of the small and large intestines, as well as in the liver. Inactivation of CYP 3A4 by grapefruit juice occurs predominantly in the small intestine; however, when grapefruit is consumed in large quantities, CYP 3A4 activity in the liver may decrease. Enzyme inactivation increases the bioavailability of certain drugs and their concentration in the blood, which can lead to overdose symptoms. Inactivating agents in grapefruit are furanocoumarins, as well as the flavonoid naringin and its metabolite naringenin, bergamottin and other components (Kanazawa S. et al., 2001; Bailey D.G. et al., 2013). The effect of grapefruit on pharmacokinetics is expressed in an increase in the maximum concentration of the drug in the blood plasma and the area under the concentration-time curve. The pharmacokinetics of drugs administered intravenously under the influence of grapefruit does not change significantly (Ducharme M.P. et al., 1995; Lundahl J. et al., 1995).

For a list of drugs that can cause side effects when used in combination with grapefruit, see D.G. Bailey et al. (2013). These include some calcium channel blockers, β-adrenergic blockers, analgesics, corticosteroids, estrogens, benzodiazepines, statins, antibiotics, antivirals (including those used for HIV infection), antineoplastic, antiallergic, psychotropic and other drugs (Kanazawa S. et al., 2001; Mahgoub A.A., 20 02; Okura T. et al., 2008; Seidegård J. et al., 2009; Nieminen T.H. et al., 2010). It is important to emphasize that the interaction with grapefruit characterizes not groups, but individual drugs. Common features of such drugs include low or moderate bioavailability (up to 70%), inactivation by the CYP 3A4 enzyme and taking per os . The clinical significance of grapefruit-drug interactions depends on the breadth of the therapeutic effect, the severity of overdose symptoms, the nature of grapefruit consumption, the age and individual characteristics of the patient (Bailey D. G. et al., 2013).

In some studies, participants received more grapefruit than they usually consume. However, when consumed in normal doses (200–250 ml of juice or one whole fruit), grapefruit may have a clinically significant effect on the effects of certain drugs. It has been reported, for example, that taking the calcium channel blocker felodipine in combination with grapefruit at the indicated dose resulted in a 3-fold increase in the systemic concentration of the drug compared to the control. When drinking grapefruit juice 250 ml 3 times a day for 6 days, taking felodipine at the usual dosage was accompanied by an approximately 5-fold increase in systemic concentration. The interval between taking grapefruit and medication also matters. The maximum effect was achieved when grapefruit was consumed less than 4 hours before taking felodipine or nisoldipine; with an increase in the interval to 24 hours, a decrease in the severity of the effect was noted to 25% after a single and 50% after repeated use of grapefruit (Lundahl J. et al., 1995; Takanaga H. et al., 2000; Bailey D.G. et al., 2013). A high individual variability of interaction was noted (Dresser G.K. et al., 2000). The effect of grapefruit depends on the individual characteristics of the organism, especially the age of the patient and the activity of the CYP 3A4 enzyme. Activity can be determined on the material of a biopsy of the small intestine, which, however, is unjustified due to the invasive nature of the procedure.

There are reports of side effects of the simultaneous use of grapefruit and various drugs due to excessive systemic concentration of the drug (Goldbart A. et al., 2000; Hermans K. et al., 2003; Dreier J.P., Endres M., 2004; Karch A.M., 2004; Grande L.A. et al., 2009; Pillai U. et al., 2009; Agosti S. et al., 2012). This topic is especially relevant for older patients who take more drugs on average and often consume grapefruit (Dresser G.K. et al., 2000; Bailey D.G. et al., 2013). Older people have fewer compensatory opportunities to neutralize drug overdose. For drugs with a significant breadth of therapeutic action, fluctuations in the concentration of a drug substance in blood plasma over a wide range may not have clinically significant consequences. On the other hand, even a moderate increase in the concentration of a drug with dose-dependent toxicity can lead to side effects. An example is the lengthening of the interval Q-T on an electrocardiogram, noted when taking some anticancer and antiarrhythmic drugs in combination with grapefruit; in this case, the development of ventricular tachycardia (torsades de pointes) is possible. Such cardiac symptoms are regarded as a contraindication to the use of grapefruit in combination with appropriate drugs, even with a moderate increase in bioavailability under its influence. This approach is also justified in case of a real risk of other complications: rhabdomyolysis, nephro- and myelotoxic effects, etc. (Mazokopakis E.E., 2008; Bailey D.G. et al., 2013). Instructions for the relevant medicinal products should contain information about interactions with grapefruit. If, despite contraindications, the patient wishes to regularly consume grapefruit, one can try to reduce the dose of the drug or replace it with another drug that does not interact with grapefruit.

Drug interactions of grapefruit are generally considered undesirable, but grapefruit’s bioavailability-enhancing properties may be of practical use. Increasing bioavailability means achieving a therapeutic effect with a lower dose of a drug at a lower systemic concentration of its metabolites. Patients who regularly consume grapefruit can be tried at a lower dose of appropriate drugs. Given the variability in the pharmacological action of grapefruit, the approach must be cautious. Let’s look at a few examples below.

there is data according to which the use of grapefruit increases the bioavailability of cyclosporine – expensive, which has been used over the years to prevent the rejection of allo -transplants (Ducharme M.P. et al., 1995; Hollander a.a. et al., 1995; Siridhan K. , Sivaramakrishnan G. , 2016). Artemether is an effective antimalarial drug, but relapses of malaria are possible with monotherapy, presumably due to a decrease in the concentration of the drug in the blood plasma under the influence of CYP 3A4. The use of grapefruit increases the bioavailability of artemether, which may be accompanied by an increase in the effectiveness of therapy (El-Lakkany N.M. et al., 2004). Of particular note is the increase in the bioavailability of some analgesics (morphine, oxycodone and diclofenac) under the action of grapefruit (Mahgoub A.A., 2002; Okura T. et al., 2008; Nieminen T.H. et al., 2010). Regarding paracetamol, the data are contradictory (Dasgupta A. et al., 2008; Qinna N.A. et al., 2016). Obviously, the topic of potentiation of the action of analgesics requires further study. An increase in the bioavailability of glucocorticoids (methylprednisolone, budesonide) under the influence of grapefruit has also been reported (Varis T. et al., 2000; Seidegård J. et al., 2009), which opens the prospect of research on grapefruit as a means of reducing the doses of hormonal drugs. A negative result was obtained for prednisolone (Hollander A.A. et al., 1995). Also of interest are the interactions of grapefruit with antibiotics: an increase in the bioavailability of erythromycin under the action of grapefruit juice has been reported; for clarithromycin, the result is negative (Hollander A.A. et al., 1995; Kanazawa S. et al., 2001). Grapefruit and its naringin have been reported to have beneficial effects on diabetes and obesity (Jung U.J. et al., 2004; Punithavathi V.R. et al., 2008; Mahmoud A.M. et al., 2012; Xulu S., Oroma Owira P.M., 2012; Alam M.A. et al., 2014; Chudnovskiy R. et al., 2014; Murunga A.N. et al., 2016; Sirovina D. et al., 2016). Further clinical and experimental studies of grapefruit interactions with antihyperglycemic drugs and insulin are needed.

The effect of grapefruit varies from patient to patient and from one study to another. Efficiency may vary depending on the variety, batch, storage conditions, juice production characteristics, which makes it difficult to dose in a narrow therapeutic window. In this regard, it seems promising to develop drugs based on grapefruit components that could be accurately dosed. Some dietary supplements from grapefruit seeds and peel are positioned as an antibacterial agent, however, data on the antibacterial properties of grapefruit are contradictory (von Woedtke T. et al., 1999; Heggers J.P. et al., 2002; Cvetnić Z., Vladimir-Knezević S., 2004; Adukwu E.C. et al., 2012).

The content of furanocoumarins, naringin and other active ingredients must be known in a grapefruit-based medicinal preparation. Naringin accumulates in young fruits; with further ripening of the grapefruit, its concentration may decrease. Inside the fruit, the maximum concentration was found in the membranes, the white layer of the peel (albedo) and the core; in pure juice the concentration is lower (Jourdan P. S. et al., 1985). Accordingly, to achieve a pharmacological effect, it is better to use whole grapefruit or natural juice with pulp; especially since the concentration of naringin (which has a bitter taste) and other components in the juices sold can be reduced.

In conclusion, we note that grapefruit and some other citrus fruits are valuable food products. At the same time, the interaction of grapefruit with certain medicinal substances leads to an increase in their bioavailability. The latter can cause symptoms of overdose, which is especially unfavorable in case of dose-dependent toxicity. Understanding the mechanisms of such interaction is important for determining indications and contraindications for the use of grapefruit in combination with various drugs in order to ensure the safety and effectiveness of therapy.

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> Interaction of grapefruit with medicinal preparations

D.J. Bailey, S.V. Yargin

Summary. In a mini-look, the main scientific concepts and clinical manifestations of the relationship between grapefruit and medicinal preparations are discussed. Grapefruit and a smaller world – hot oranges, pomelo and lime can be combined with some common medical practices. The main active ingredient, perhaps, is furanocoumarin. Oranges of licorice varieties of furanocoumarins should not be taken. The interaction is based on inactivation of the CYP 3A4 enzyme, which takes part in the metabolism of rich metabolites. Some clinically significant side effects are discussed. The interaction of grapefruit with faces as a whole is viewed as an unbelievable phenomenon, protesting the power of grapefruit to increase bioavailability can be known in practice by reducing the doses of medicinal preparations. The pharmacological action of grapefruit is subject to significant infusions, which are due to the difficulties of dosing in the minds of a narrow therapeutic field. At the same time, it is important to note the prospective distribution of pharmaceutical preparations based on the components of grapefruit, which could be more accurately dosed. Also grapefruit, as well as other citrus fruits, is a valuable food product. At one time, yoga interactions with certain medicinal preparations can lead to symptoms of overdose. The explanation of these mechanisms may be significant for the indication and contraindication to the survival of grapefruits in other medical conditions.