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How Fruit Juice Interacts With Common Medicines
How Fruit Juice Interacts With Common Medicines
DRUG INTERACTIONS
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-
SUMMARY BOX
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LEARNING
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
PANEL
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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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
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.
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.
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
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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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References
Health 2008;128:324326.
15. Committee on Safety of Medicines/Medicines
1997;2:103121.
Pharmacol Ther2002;71:1120.
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