Drug-grapefruit juice interactionsBMJ 2013; 346 doi: https://doi.org/10.1136/bmj.f1 (Published 07 January 2013) Cite this as: BMJ 2013;346:f1
- Munir Pirmohamed, professor of clinical pharmacology
- 1Wolfson Centre for Personalised Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GL, UK
Grapefruit juice, which is widely consumed for its positive health benefits, can have severe, sometimes fatal, interactions with drugs. This phenomenon was first identified serendipitously about 20 years ago for the calcium channel antagonist felodipine,1 and a recent review found that more than 85 drugs can be affected by grapefruit juice.2 Two main mechanisms, which have different clinical consequences, have been defined (table⇓).
Firstly, grapefruit juice contains furanocoumarins (such as 6′,7′-dihydroxybergamottin),3 which can cause irreversible inhibition of the cytochrome P450 enzyme, CYP3A4, mainly in the small intestine.4 CYP3A4 is involved in the metabolism of around 50% of drugs, so a wide variety of drugs can be affected by the consumption of grapefruit juice. The net effect is a reduction in the pre-systemic metabolism of these drugs, which increases their systemic exposure, sometimes by more than 700% (as has been shown for simvastatin).5 Because inhibition of CYP3A4 is irreversible, it can last for longer than three days after ingestion of grapefruit juice, until new enzyme has been synthesised in the gut wall.2
The interaction can occur after ingestion of freshly squeezed juice, juice from concentrate (as little as 200 mL), and consumption of the fruit itself.5 The effect on drug pharmacokinetics seems to be greater with regular consumption. The clinical consequences can vary from an asymptomatic increase in drug concentrations to life threatening events.2 5 Such a life threatening event is described in a case report of impaired metabolism of amiodarone after ingestion of grapefruit juice that led to an increase in QT interval and torsades de pointes.6 Similarly, rhabdomyolysis has been described after co-ingestion of grapefruit juice with atorvastatin.7
A second mechanism involves the inhibition of a member of the influx transporter protein family (organic anion transporter polypeptide; OATP) by grapefruit.8 Flavonoids such as naringin and hesperidin have been implicated in the mechanism of OATP inhibition. The net effect is reduced bioavailability of the drug, with a decrease in its systemic and tissue concentrations and thus a decrease in its efficacy. In contrast to the effect of grapefruit juice on CYP3A4, the inhibition of OATPs shows a clear volume (dose)-response association, which is competitive in nature, with inhibition lasting about four hours. Thus, a simple way to avoid this interaction is to have a four hour gap between the intake of grapefruit juice and drug administration.8 Drugs affected through this mechanism include aliskiren, celiprolol, fexofenadine, and ciprofloxacin.
The clinical consequences of both types of interaction are difficult to predict for individual patients. Sequelae depend on the bioavailability of the drug, the intrinsic level of expression of CYP3A4 or OATPs in the gut, the amount and frequency of grapefruit juice consumption, and the characteristics of the grapefruit juice ingested (fruit species, geographical origin, maturity, manufacturing processes, storage conditions, and seasonal variability).2 5 8 The first of the two mechanisms is most important clinically because of the serious toxic effects that can arise with certain drugs and because the inhibition is irreversible. It is therefore important to ask patients about consumption of grapefruit juice, to document this in the clinical notes, and to provide information on avoiding grapefruit juice, particularly if drugs have a narrow therapeutic index or toxic manifestations that can be severe. For some drugs that are known to interact with grapefruit juice, it has been proposed that the dose given may be reduced; however, it is difficult to predict the consequences of an interaction for different people taking the same drug.2 Thus, it is probably wise to prescribe an alternative drug that is not affected by grapefruit juice consumption.
The table lists the commonly used drugs that are affected by grapefruit juice, but many other drugs can also be affected. Further information can be obtained from other sources such as the British National Formulary (appendix 1). More research is needed to define which other drugs currently on the market can be affected by grapefruit juice, and to develop better methods to assess the severity of the interaction for different people. Efforts to reduce the furanocoumarin content of grapefruit juice are also under way through crossbreeding,9 alternative processing techniques,10 and the use of edible fungi.11
Finally, although this editorial has focused on grapefruit juice, furanocoumarins are also present in Seville oranges and pomelos. Furthermore, other fruits and juices, including cranberry, Goji berry, and apple, contain other active moieties that can affect different P450 isoforms and transporters and interact with different drugs. It is therefore important to take a careful dietary history from patients and provide them with the relevant information to minimise the effects of these potentially serious interactions.
Cite this as: BMJ 2013;346:f1
Competing interests: The author has completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declares: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.
Provenance and peer review: Commissioned; not externally peer reviewed.
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