Prescription drugs and grapefruit a 'deadly mix'

“A breakfast of grapefruit and marmalade on toast could be lethal for people taking medication” is the headline in the Daily Mail.

The news is based on a review that has highlighted grapefruit-medication interactions that can cause serious side effects.

It is already known that grapefruits contain a group of chemicals, furanocoumarins, which can affect drug metabolism – the amount of time it takes for a drug to be broken down by the body.

The chemical inhibits an enzyme that breaks down drugs, this can cause more ‘active’ drug to be present in the body than was intended with the given dose. This can then trigger unpleasant, and sometimes serious, side effects.

However, the authors state that there is a general lack of knowledge about this interaction in the healthcare community, despite the fact that an interaction between grapefruit and certain medications was discovered more than 20 years ago.

The number of drugs that could potentially interact with grapefruit to cause serious adverse events has been increasing. The researchers say that there are now 43 types of prescription medication that could cause serious side effects if taken with grapefruit (or grapefruit juice).

What is the basis for these reports?

Researchers from Canada have published a narrative review (a review that discusses and summarises the literature on a particular topic) of grapefruit-medication interactions in the peer-reviewed Canadian Medical Association Journal.

Grapefruit contains a class of chemicals known to inhibit the process by which a number of drugs are broken down by the body (inactivated).

This causes the concentration of drugs in the body to be higher than it should be, which can cause side effects.

The researchers state that more than 85 drugs available in Canada have the possibility of interacting with grapefruit. The number of drugs which could potentially interact with grapefruit and lead to serious side effects has recently increased to 43 as new drugs come on the market.

While not addressed by the researchers, it is likely that broadly similar figures would apply to the UK market.

How can grapefruit interact with medications?

The authors report that grapefruit, grapefruit juice, and some other citrus fruit, including Seville oranges, limes and pomelos, contain a class of chemical called furanocoumarins. Furanocoumarins inhibit an enzyme, cytochrome P450 3A4, that is responsible for the inactivation of approximately half of all drugs.

This enzyme is found in the lining of the gut and in the liver. Furanocoumarins in grapefruit mainly inhibit cytochrome P450 3A4 in the gut.

This means that if a drug that is normally broken down by cytochrome P450 3A4 is taken at the same time as grapefruit, more ‘active’ drug will be absorbed by the body, as less will have been inactivated by the enzyme.

The prescribed dose of these drugs takes into account the fact that some of the drug will be inactivated by P450 3A4. So if this doesn’t occur, it leads to the person being exposed to higher concentrations of the drug than was intended, and this can have adverse effects.

Furanocoumarins are not present in varieties of sweet orange, such as naval or Valencia oranges.

How much grapefruit is too much grapefruit?

The researchers report that furanocoumarins are present in all forms of grapefruit (freshly squeezed juice, frozen concentrate and whole fruit).

One whole grapefruit or 200ml of juice is sufficient to cause enough of an increase in the concentrations of active drugs to have an effect on the body, and therefore could cause side effects.

The time between consuming grapefruit and taking the medication, and the frequency of consumption of grapefruit, can also influence their effect.

The researchers recommend that it is better to err on the side of caution and never have any grapefruit (or other citrus fruit containing furanocoumarins) when taking drugs known to interact with these types of fruit.

What medications are known, or predicted, to interact with grapefruit?

Drugs that interact with grapefruit are:

taken orally (by mouth)
inactivated by the enzyme P450 3A4
usually given in a dose which accounts for inactivation by P450 3A4

The researchers provide a list of drugs that are predicted to interact with grapefruit, including:

Drugs used to treat cancer (crizotinib, dasatinib, erlotinib,everolimus, lapatinib, nilotinib, pazopanib, sunitinib, vandetanib, vemurafenib)
Drugs used to treat or prevent infections (erythromycin, halofantrine, maraviroc, primaquine, quinine, rilpivirine)
Drugs used to treat high cholesterol (atorvastatin, lovastatin, simvastatin)
Drugs used to treat heart and blood vessel conditions (amiodarone, apixaban, clopidogrel, dronedarone, eplerenone, felodipine, nifedipine, quinidine, rivaroxaban, ticagrelor)
Drugs affecting the central nervous system (oral alfentanil, buspirone, dextromethorphan, oral fentanyl, oral ketamine, lurasidone, oxycodone, pimozide, quetiapine, triazolam, ziprasidone)
Drugs used to treat nausea (domperidone)
Immunosuppressants (cyclosporine, everolimus, sirolimus, tacrolimus)
Drugs used to treat urinary tract conditions (darifenacin, fesoterodine, solifenain, silodosin, tamsulosin)

What serious side effects can occur due to grapefruit-drug interactions?

The researchers identified the following examples of cases of potentially serious adverse events that have been reported in published literature as a result of grapefruit-drug interactions:

Torsade de pointes (a form of abnormally rapid heartbeat that starts in the lower chambers of the heart, which can increase the risk of sudden death) has been reported when amiodarone or quinine are taken in conjunction with, or after, high volumes or regular consumption of grapefruit juice
Complete heart block (where there is no transmission of the electrical pulses between the upper and lower chambers of the heart that are needed to make it beat), reported with verapamil, when taken after a high volume of grapefruit juice had been drunk during preceding days
Rhabdomyolysis (breakdown of muscle fibres that leads to the release of muscle fibre contents, including myoglobin which breaks down into substances that can damage the kidney), had been reported when atorvastatin was taken with daily grapefruit juice, and when simvastatin was taken when the patient was also eating whole grapefruit daily
Nephrotoxicity (kidney damage) has been reported when a large amount of grapefruit marmalade was eaten in the week prior to taking tacrolimus
Myelotoxicity (damage to the bone marrow) has been reported when colchicine was taken after drinking a high volume of juice (one litre a day) over the preceding two months
Venous thrombosis (blood clot) was reported when ethinylestradiol was taken after whole grapefruit had been eaten daily over the preceding three days

Are certain people more vulnerable?

What makes an individual person more vulnerable to interactions between grapefruit and their medications is not well understood, but it may depend on the:

levels of P450 3A4 normally present in their gut
drug being taken – with some drugs, the risk of interaction is higher than others
patient’s age – this is due to a number of factors, including biological changes with age, also, those aged over 45 are reported to be more likely to buy grapefruit and also to take medications

How common are adverse effects due to grapefruit-medication interactions?

The simple answer to this is that nobody is really sure. The researchers state that data is not available to be able to estimate how common grapefruit-drug interactions are in routine practice.

They say that this is because there is a lack of knowledge about grapefruit-medication interactions in the healthcare community, resulting in under-reporting of these interactions.

In the UK, adverse reactions to medication are monitored by the MHRA’s Yellow Card Scheme, but currently, the monitoring system used by the scheme does not collect information on grapefruit consumption.

Also, the researchers did not comment on how frequently grapefruit-medication interactions resulted in death.

What should I do about this issue?

Read the patient information leaflet that comes with your medicine, and follow the instructions for how it should be taken and what foods should be avoided.
When being prescribed a new medication, discuss with your doctor or pharmacist whether there are any foods or drinks you should avoid if you are concerned that your diet may affect your medication.