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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. Many 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 concentrate . This article is not an exhaustive list of all Orange juice and medicine juice and drug interactions. It is not certain which compounds are responsible for interacting with medicines.
Cytochrome P enzymes CYP can be inhibited by fruit juices. Naringin, which is metabolised to naringenin, is known to inhibit the isoenzyme CYP3A4. However, the variability between different grapefruit juice products means its effects on medicines can be unpredictable. This means drinking grapefruit juice does not substantially affect the exposure of medicines metabolised by CYP3A4 if they are given intravenously. 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 already-absorbed medicines e. 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 medicines .
Patients taking medicines that interact with fruit juices may ask whether they should avoid the fruit itself. However, a case study found that ingestion of a grapefruit g before taking either amlodipine or nifedipine had no effect on the plasma concentration of either drug . Until more is known, pharmacists should advise patients to avoid the whole fruit if there is evidence its juice can interact with their medicine.
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. Grapefruit juice moderately increases felodipine exposure.
This is an established interaction and concurrent use is contraindicated. Patients taking felodipine should not eat whole grapefruit. 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.
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 recommendedand a small quantity of grapefruit juice is consumed at breakfast.
However, concurrent use is still not recommended. Grapefruit juice moderately increases atorvastatin exposure, but the interaction seems less likely to be clinically relevant than Orange juice and medicine with simvastatin. The UK manufacturer suggests that large quantities of grapefruit juice more than 1. 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.
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 absorption . The importance of this interaction is unclear. Pharmacists should ask patients who experience unexpected changes in ciclosporin concentrations about recent changes to their diet. 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 is predominantly metabolised by CYP3A4 and has only moderate oral bioavailability. Nevertheless, it appears that its absorption is not increased ificantly by grapefruit juice in most patients. In one study, ml of grapefruit juice was given to healthy subjects one hour before and together with a 50mg dose of sildenafil. 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 Orange juice and medicine should be told to be alert for adverse effects e. Pomelo fruits are related to grapefruits, but appear to have the opposite effect on sildenafil metabolism.
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 Orange juice and medicine might be less effective if taken with pomelo juice. Fexofenadine is transported by both P-glycoprotein and OATPs, and changes in their function can affect fexofenadine uptake. In particular, OATPs are inhibited by grapefruit juice, apple juice and orange juice, potentially reducing the absorption of fexofenadine .
Similarly, another study in 10 healthy subjects consuming 1. 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. 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 ml of grapefruit juice three times a day for five days, with a single mg dose of aliskiren on day three.
Another study repeated the experiment, with 12 healthy people drinking ml of apple juice, orange juice or water three times daily for five days, with a single mg dose of aliskiren on day three. The exact mechanisms for these interactions are unclear. The UK manufacturer of aliskiren suggests that the interaction is Orange juice and medicine 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. Inthe 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 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 bleeding . 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 effects . However, in five 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 activity .
It has been suggested that an interaction might be taking place through a pharmacodynamic mechanism; for example, salicylates in commercial cranberry juice might cause hypoprothrombinaemia . 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 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 vitro . 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 interaction.
Pharmacists should consider pomegranate juice consumption in a patient with otherwise unexplained increase in INR or fluctuations of INR. The book is available in print through Pharmaceutical Press or electronically with quarterly updates through MedicinesComplete. This article was amended on 10 October to clarify that simvastatin should not be taken with grapefruit juice even if simvastatin is taken in the evening and grapefruit juice is consumed in the morning.
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