Download grapefruit interactions

MAY 2013
GRAPEFRUIT INTERACTIONS
G
rapefruit and other juices can interact with many
medicines, affecting either the efficacy or causing
adverse effects.
Although the potential for drug-interactions involving
grapefruit juice has been known for over twenty years, a
recent report from Canadian researchers in the Canadian
Medical Association Journal increased the awareness
of grapefruit drug-interactions with more than 85
medications now known to interact with grapefruit
juice. The report noted that the number of medications
identified as interacting with grapefruit has doubled
with potentially fatal interactions increasing from 17 to
43 in the past four years (2008 – 2012). The researchers
identified 43 medications which can cause serious side
effects.
Serious side effects have occurred when certain medicines
are taken with grapefruit, including:
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complete heart block (resulting in a very slow
heart beat)
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torsade de pointes (rapid heartbeats that can
lead to sudden death)
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rhabdomyolysis (severe damage to skeletal
muscle that can lead to kidney damage)
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nephrotoxicity (kidney damage)
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myelotoxicity (damage to bone marrow)
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respiratory depression (reduced or slowed
breathing).
Commonly used medications implicated include certain
cholesterol-lowering medications, blood pressure
medications, cancer treatments, immunosuppressant
agents, and some antibiotics and antivirals.
Examples include (note this list is not exhaustive):
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Atorvastatin, simvastatin
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Colchicine
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Amiodarone
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Erythromycin
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Cyclosporin
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Domperidone (Motilium)
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Eplerenone (Inspra)
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alcium channel blockers e.g. felodipine, losartan,
C
nifedipine, verapamil, lercanidipine
Anticoagulants e.g. rivaroxaban (Xarelto)
Platelet aggregation inhibitor e.g. ticagrelor
(Brilinta), clopidogrel (Plavix, Iscover)
Sildenafil (Viagra), vardenafil (Levitra)
Urinary tract agents e.g. darifenacin (Enablex),
Solifenacin (Vesicare), tamsulosin (Flomaxtra)
Mechanism of action
Grapefruit drug-interactions occur due to interference
with the liver enzyme known as cytochrome P450 3A4
(CYP3A4). This enzyme is responsible for the metabolism
of about 50% of all medicines. With these enzymes
inhibited by grapefruit, medication concentrations can
increase rapidly and lead to potentially toxic effects.
CYP3A4 is located in epithelial cells (enterocytes) lining
the small intestines and colon, and in the parenchymal
cells of the liver (hepatocytes).
The substance in grapefruit involved in this
interaction are the furanocoumarins, specifically
6,7-dihydroxybergamottin. Freshly squeezed juice,
canned or bottled juice and whole fruit can cause an
interaction.
Near maximal inhibition of gut CYP3A4 occurs with just
one glass of grapefruit juice or one whole grapefruit. The
potential for these drug interactions can exist for 48 to
72 hours after the last exposure to grapefruit juice. This
is because a new enzyme has to be synthesised in the gut
wall, which takes around 3 days.
As a result, medications which interact with grapefruit
can’t just be separated by a few hours to avoid the
potential for these effects. Residents taking medications
known to significantly interact with grapefruit should
avoid grapefruit and grapefruit juice entirely.
In many cases alternative medications may be available
for those patients who do not want to stop consuming
grapefruit.
GRAPEFRUIT INTERACTIONS
Examples of grapefruit interactions
Blood levels of ticagrelor are more than doubled by
grapefruit juice, leading to an enhanced and prolonged
antiplatelet effect.
The combination of grapefruit juice and amiodarone in
one case led to bradycardia and marked QT prolongation
associated with ventricular arrhythmias, including an
episode of torsade de pointes requiring immediate
electrical cardioversion. This lady had been drinking
about one litre of juice daily.
Felodipine combined with just one glass of grapefruit had
an average systemic drug concentration that was 3-fold
that seen with water.
The systemic concentration of cholesterol-lowering
drug simvastatin is increased by 330% when combined
with a 200mL glass of grapefruit juice once a day for 3
days, compared with water. This can lead to muscle
weakness and pain (myopathy) or rhabdomylosis with
life-threatening muscle injury and possible kidney failure.
Not all statins interact with grapefruit – only simvastatin
and to a lesser extent atorvastatin. Pravastatin, fluvastatin
and rosuvastatin do not interact.
Apple and orange juice interactions
Fruit juices may also decrease the oral absorption of
drugs by inhibiting intestinal drug transport.
Grapefruit, apple juice and orange juice are potent
inhibitors of organic anion-transporting polypeptides
(OATP). OATPs transport drugs across the cell membrane,
particularly in the liver and kidney. This interaction
with fruit juices diminishes the oral drug bioavailability
(fraction of an administered dose of unchanged drug
that reaches the systemic circulation) through inhibition
of uptake transport, thereby reducing the effectiveness
of the medication. The constituent in grapefruit which
inhibits OATP is the bioflavonoid naringin.
For example, routine intake of thyroxine with grapefruit
or orange juice might result in a reduction in blood
concentration sufficient to induce under-treatment.
Apple and orange juice can decrease the amount of
atenolol available from a dose. Orange juice reduces the
blood concentration of a dose of atenolol by about half.
About three glasses (600mL) of apple juice taken over
one and a half hours can reduce the amount of atenolol
in the blood stream by over half (58%). This effect with
apple juice appears to be enhanced with larger amounts
of apple juice. Ingestion of 1200 mL apple juice consumed
over 3 hours reduces the amount of atenolol by 82%.
Apple juice reduces the amount of the antihistamine
fexofenadine (Telfast) reaching the blood stream by three-
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quarters. Grapefruit juice reduces it by approximately
one-half. These interactions can lead to a lack of effect of
the antihistamine.
In contrast to CYP3A4 interactions, OATP-mediated fruit
juice interactions may potentially be avoided by separating
medicine and juice consumption by at least four hours.
Other fruit interactions
The effect is not limited to grapefruit. Other less-sweet
citrus fruits such as Seville oranges (often used in
marmalades), limes, star fruit, tangelos and pomelos also
contain the active ingredients furanocoumarins.
Management of interactions
It is not practical to eat a consistent amount of fruit or
juice to avoid interactions with grapefruit. Fruit species,
geographical origin, maturity, manufacturing process,
storage conditions, and seasonal variability will all
affect the amount of furanocoumarins. People who take
medicines that may interact with grapefruit are usually
advised not to eat grapefruit or drink grapefruit juice at
all.
Interactions with grapefruit, apple and orange juice by
the OATP mechanism (e.g. thyroxine, atenolol) can be
managed by separating the juice and medication by at
least 4 hours.
A Residential Medication Management Review (RMMR)
by a pharmacist will help identify medications known to
interact with grapefruit and provide recommendations
for alternate medications.
For more information see http://www.nps.org.au/
publications/consumer/medicinewise-living/2012/
mixing-grapefruit-with-medicines
References
Br J Clin Pharmacol 2010;70(5):645-655.
Br J Clin Pharmacol 2004;58:56-60.
Br J Clin Pharmacol 2013;75(1):172-9.
Eur J Clin Pharmacol 2005;61:337-40.
Clinical Pharmacology & Therapeutics 2007;81:362-370.
Am J Emerg Med 2012;30:248.e5-e8.