LEARNING

DRUG INTERACTIONS

How fruit juice interacts

with common medicines
Fruit juices contain several pharmacologically active compounds.
Whether these can interfere with the metabolism of medicines is
the subject of much research, but uncertainty remains.

ADAM WARD / DREAMSTIME.COM

STEPHANIE JONES, CLAIRE L PRESTON AND HARPREET SANDHU

any fruits and fruit juices, in particular citrus juices, can affect the
metabolism of medicines. Interactions have been documented with apple,
cranberry, grapefruit, orange, pomegranate, pomelo and purple grape juices.
However, while the area has been subject to much research, it is often hard to
predict whether an interaction will occur with a particular fruit product. This is
because the concentrations of the natural
compounds in the juice vary between different varieties of fruit and can be affected
by environmental conditions, such as the
climate where the fruit is grown.
The profile of compounds in citrus juice
can also be affected by commercial juicing procedures. For example, mechanical
pressing increases contact between the
peel and the pith of the fruit, which have
a much higher concentration of naringin
than the juice vesicles. Compounds can
also be affected by turning the juice into
a concentrate1.
This article is not an exhaustive list of
all fruit juice and drug interactions. Further interactions are available in Stockleys Drug Interactions.

Causes of interactions
Fruit juices contain several pharmacologically active compounds. These include fla-

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SUMMARY BOX

In this article you will learn:

hy fruit juices interact with certain

Wmedicines
medicines that interact
Cwithommon
grapefruit juice
he latest advice on fruit juice for
Tpatients
taking warfarin

Pomegranate and other citrus fruit juices

can affect the metabolism of several
common medicines
vonoids (such as naringin and hesperidin)
and furanocoumarins (such as bergamottin and 6,7-dihydroxybergamottin). It is
not certain which compounds are responsible for interacting with medicines.
Cytochrome P450 enzymes (CYP) can
be inhibited by fruit juices. Naringin,
which is metabolised to naringenin, is
known to inhibit the isoenzyme CYP3A4.
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Bergamottin and 6,7-dihydroxybergamottin can also cause CYP3A4 inhibition.

Grapefruit juice is known to be a weak
inhibitor of CYP3A4 and is therefore expected to increase the exposure of medicines

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metabolised by CYP3A4. However, the

variability between different grapefruit
juice products means its effects on medicines can be unpredictable.
Grapefruit juice exerts the majority of
its inhibitory effect on CYP3A4 in the intestine, but has minimal effect on hepatic
CYP3A4. This means drinking grapefruit
juice does not substantially affect the
exposure of medicines metabolised by
CYP3A4 if they are given intravenously.
Grapefruit juice has the greatest effect on
drugs that have poor oral bioavailability,
such as felodipine (see Common grapefruit juice interactions).
P-glycoproteins are thought to be inhibited by furanocoumarins. P-glycoprotein is an efflux pump (responsible for
moving substances out of the cell) found
in some cell membranes.
P-glycoprotein in the cells of the gastrointestinal wall can eject some alreadyabsorbed medicines (e.g. fexofenadine)
back into the intestine, so its inhibition
increases the patients overall exposure to
affected medicines.
Organic anion-transporting polypeptides (OATPs) can be inhibited by juices
including grapefruit, apple and orange
juice. These are membrane transport proteins responsible for substance uptake, for
example through the gastrointestinal wall.
This inhibition will decrease the absorption of affected medicines2.
Although the causes of fruit juice interactions have not been determined conclusively, studies have investigated fruit
juice interactions in several commonly
prescribed medicines to determine their
effects.

Sildenafil
Sildenafil is predominantly metabolised
by CYP3A4 and has only moderate oral
bioavailability. Nevertheless, it appears
that its absorption is not increased significantly by grapefruit juice in most patients.
In one study, 250ml of grapefruit juice
was given to healthy subjects one hour
before and together with a 50mg dose
of sildenafil. The area under the concentration-time curve (AUC) for sildenafil,
a measure of overall exposure, was increased slightly (by 23%), and the maximum plasma concentration was not
changed significantly7.
However, a case report has described
one patient who experienced a 168% increase in the AUC for sildenafil after taking a single 25mg dose of sildenafil with
250ml of grapefruit juice8.
The minor pharmacokinetic interaction of grapefruit juice with sildenafil is
unlikely to be clinically important in most
patients. Nevertheless, the combination
should be avoided. Patients who decide to
drink grapefruit juice while taking silde370

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PANEL

Do whole fruits interact?

Patients taking medicines that interact
with fruit juices may ask whether they
should avoid the fruit itself.
Studies have shown that consuming
grapefruit pulp, grapefruit segments,
or grapefruit segment-free extract
can increase a patients exposure,
as measured by the area under the
concentration-time curve (AUC), to
nifedipine and nisoldipine by 30%, and
results in a threefold increase in exposure
to felodipine3, 4. However, a case study
found that ingestion of a grapefruit
(300g) before taking either amlodipine
or nifedipine had no effect on the plasma
concentration of either drug5.
Until more is known, pharmacists
should advise patients to avoid the
whole fruit if there is evidence its juice
can interact with their medicine.

Small amounts of
apple, grapefruit and
orange juices can have
a sizeable effect on
aliskiren exposure
and concentrations
nafil should be told to be alert for adverse
effects (e.g. headache, flushing, hypotension) and avoid drinking grapefruit juice if
these occur.
Pomelo fruits are related to grapefruits,
but appear to have the opposite effect
on sildenafil metabolism. In a crossover
study, when healthy subjects took a single 50mg dose of sildenafil with 250ml of
pomelo (Citrus grandis) juice, the maximum plasma concentrations and AUC
were reduced by 37% and 40% respectively when compared with sildenafil
plus water9.
This finding was unexpected, particularly because pomelo juice increases
the bioavailability of ciclosporin, another
medicine metabolised by CYP3A4. This
means other mechanisms of interaction could be involved and, until more is
known, patients should be advised that
sildenafil might be less effective if taken
with pomelo juice.

Fexofenadine
Fexofenadine is transported by both Pglycoprotein and OATPs, and changes
in their function can affect fexofenadine
uptake. In particular, OATPs are inhibited

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11 OCTOBER 2014

by grapefruit juice, apple juice and orange

juice, potentially reducing the absorption
of fexofenadine10.
One study found that 300ml of normal
strength grapefruit juice reduced the AUC
of a single 120mg dose of fexofenadine by
42%, and 1.2 litres of grapefruit juice was
found to reduce the AUC by 64%11.
Similarly, another study in 10 healthy
subjects consuming 1.2 litres of juice found
that grapefruit juice at normal strength
decreased the AUC of a single 120mg
dose of fexofenadine by 67%, while dilute grapefruit juice caused a smaller reduction of 23%. Normal strength orange
juice and apple juice also decreased the
AUC of fexofenadine, by 72% and 77%,
respectively10.
The amounts of fruit juice consumed
in these two studies were quite large, and
the effect on fexofenadine exposure might
not be as great for patients only drinking a
small amount.
Further study is required to determine
the clinical relevance, if any, of the reduction in fexofenadine bioavailability in the
presence of grapefruit juice, orange juice
and apple juice. Patients taking fexofenadine do not need to avoid fruit juices. However, pharmacists should consider this interaction as a possible cause if treatment
seems less effective than expected.

Aliskiren
Studies have shown that small amounts
of apple, grapefruit and orange juices
can have a sizeable effect on aliskiren
exposure and concentrations. It therefore seems likely that concurrent use
might reduce the blood pressure lowering
effects of aliskiren.
In a randomised, crossover study,
11 healthy people were given 200ml of
grapefruit juice three times a day for five
days, with a single 150mg dose of aliskiren
on day three. Grapefruit juice reduced the
maximum plasma concentration and AUC
of aliskiren by 81% and 61%, respectively12.
Another study repeated the experiment,
with 12 healthy people drinking 200ml
of apple juice, orange juice or water three
times daily for five days, with a single
150mg dose of aliskiren on day three.
Apple juice reduced maximum plasma
concentration and AUC by 84% and 63%,
respectively, while orange juice reduced
maximum plasma concentration and AUC
by 80% and 62%, respectively13.
The exact mechanisms for these interactions are unclear. The UK manufacturer
of aliskiren suggests that the interaction is likely to be due to an inhibition of
OATP-mediated uptake of aliskiren in the
gastrointestinal tract. Consequently, fruit
juices should not be taken with aliskiren
because of the risk that treatment may
not be effective.

LEARNING

TABLE

Common grapefruit juice interactions

Interaction

Management

Amiodarone

l Grapefruit juice inhibits the metabolism of oral amiodarone. This is an established interaction,
although the clinical consequences are still unclear. The US and UK manufacturers recommend
that grapefruit juice should be avoided when patients are taking oral amiodarone.

Calcium channel blockers

l Grapefruit juice moderately increases felodipine exposure. This is an established interaction

and concurrent use is contraindicated. Patients taking felodipine should not eat whole grapefruit.
l Studies suggest that grapefruit juice and calcium-channel blockers other than felodipine and
possibly nifedipine can be used concurrently. However, pharmacists should check the diet of any
patient who complains of increased or excessive adverse effects with any calcium channel blocker.

Statins

l Grapefruit juice has been shown to increase simvastatin exposure when large amounts are taken
at the same time. On the basis of the available data, simvastatin should not be taken simultaneously
with grapefruit juice. The interaction can be minimised, but not eliminated, if simvastatin is taken in
the evening (as recommended), and a small quantity of grapefruit juice is consumed at breakfast.
l Grapefruit juice moderately increases atorvastatin exposure, but the interaction seems less likely
to be clinically relevant than that with simvastatin. The UK manufacturer suggests that large quantities
of grapefruit juice (more than 1.2 litres daily) are not recommended.
l Grapefruit juice is not known to interact with fluvastatin, rosuvastatin or pravastatin.
l In general, the occasional glass of grapefruit juice would not appear to be a problem.

Ciclosporin

l Grapefruit juice can increase ciclosporin exposure. This is an established interaction that is
clinically important. Patients taking ciclosporin should be warned not to drink grapefruit juice, as
increased ciclosporin concentrations are associated with nephrotoxicity.
l A study has also shown that ciclosporin concentrations can be reduced if taken with purple grape
juice, which the study authors suggest is possibly due to the juice affecting ciclosporin absorption6.
The importance of this interaction is unclear. Pharmacists should ask patients who experience
unexpected changes in ciclosporin concentrations about recent changes to their diet.

Source: Stockleys Drug Interactions

Warfarin
In 2004, the Committee on Safety of Medicines (CSM) of the Medicines and Healthcare products Regulatory Agency (MHRA)
advised that patients taking warfarin
should avoid drinking cranberry juice unless the health benefits were considered to
outweigh any risks. The CSM also recommended increased international normalised ratio (INR) monitoring for any patient
taking warfarin who has a regular intake
of cranberry juice, and similar precautions
with other cranberry products (such as
capsules or concentrates). This precaution
was based upon a number of case reports
that suggested cranberry juice increased
the INR of patients taking warfarin, and had
resulted in the death of one patient from
gastrointestinal and pericardial bleeding14.
The mechanism by which cranberry
juice and warfarin interact is not known.
It has been suggested that cranberry juice
might inhibit the activity of CYP2C9, by
which warfarin is metabolised, thereby
reducing its clearance from the body and
increasing its effects15. However, in five

Patients taking warfarin are advised to avoid

drinking cranberry juice unless the health
benefits are considered to outweigh any risks
controlled studies carried out since the
CSM warning, cranberry juice or cranberry extracts have not been found to alter the pharmacokinetics of warfarin, and
cranberry juice had no effect on the pharmacokinetics of flurbiprofen, a drug used
as a surrogate index of CYP2C9 activity16.It has been suggested that an interaction might be taking place through a pharmacodynamic mechanism; for example,
salicylates in commercial cranberry juice
might cause hypoprothrombinaemia17.
Currently, the manufacturers of warfarin suggest avoiding cranberry products or
increasing the supervision and INR monitoring for patients wishing to take warfarin
and cranberry. However, the controlled
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studies now available do provide some reassurance that, in otherwise healthy individuals, moderate doses of cranberry juice
are unlikely to have an important impact
on anticoagulation control.
Case reports also suggest that pomegranate juice might increase the INR in patients taking warfarin. Pomegranate juice
has been shown to be an inhibitor of CYP2C9, the main isoenzyme involved in the
metabolism of the more active S-isomer of
warfarin, in vitro18. It is therefore possible
that pomegranate juice decreases warfarin metabolism, increasing its concentration and effects. However, the evidence is
limited to isolated case reports and controlled studies are required to confirm an

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interaction. Pharmacists should consider

pomegranate juice consumption in a patient with otherwise unexplained increase
in INR or fluctuations of INR.

pharmacokinetics of sildenafil. Clin Pharmacol

Ther 2002;71:2129.
8. Sheu MT, Wu AB, Yeh GCet al. Development of a

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About the authors

This article has been produced
by Stephanie Jones MPharm,
MRPharmS, Claire Preston BPharm,
PGDipMedMan, MRPharmS and
Harpreet Sandhu MPharm, MRPharmS
on behalf of the Stockleys Drug
Interactions editorial team. The book is
available in print through Pharmaceutical
Press or electronically with quarterly
updates through MedicinesComplete.