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BMJ 2013;346:f1 doi: 10.1136/bmj.f1 (Published 7 January 2013) EDITORIALS
Drug-grapefruit juice interactions
Two mechanisms are clear but individual responses vary Munir Pirmohamed professor of clinical pharmacology Wolfson Centre for Personalised Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GL, UK Grapefruit juice, which is widely consumed for its positive way to avoid this interaction is to have a four hour gap between health benefits, can have severe, sometimes fatal, interactions the intake of grapefruit juice and drug administration.8 Drugs with drugs. This phenomenon was first identified serendipitously affected through this mechanism include aliskiren, celiprolol, about 20 years ago for the calcium channel antagonist felodipine,1 and a recent review found that more than 85 drugs The clinical consequences of both types of interaction are can be affected by grapefruit juice.2 Two main mechanisms, difficult to predict for individual patients. Sequelae depend on which have different clinical consequences, have been defined the bioavailability of the drug, the intrinsic level of expression of CYP3A4 or OATPs in the gut, the amount and frequency of Firstly, grapefruit juice contains furanocoumarins (such as grapefruit juice consumption, and the characteristics of the 6′,7′-dihydroxybergamottin),3 which can cause irreversible grapefruit juice ingested (fruit species, geographical origin, inhibition of the cytochrome P450 enzyme, CYP3A4, mainly maturity, manufacturing processes, storage conditions, and in the small intestine.4 CYP3A4 is involved in the metabolism seasonal variability).2 5 8 The first of the two mechanisms is most of around 50% of drugs, so a wide variety of drugs can be important clinically because of the serious toxic effects that can affected by the consumption of grapefruit juice. The net effect arise with certain drugs and because the inhibition is irreversible.
is a reduction in the pre-systemic metabolism of these drugs, It is therefore important to ask patients about consumption of which increases their systemic exposure, sometimes by more grapefruit juice, to document this in the clinical notes, and to than 700% (as has been shown for simvastatin).5 Because provide information on avoiding grapefruit juice, particularly inhibition of CYP3A4 is irreversible, it can last for longer than if drugs have a narrow therapeutic index or toxic manifestations three days after ingestion of grapefruit juice, until new enzyme that can be severe. For some drugs that are known to interact with grapefruit juice, it has been proposed that the dose given The interaction can occur after ingestion of freshly squeezed may be reduced; however, it is difficult to predict the juice, juice from concentrate (as little as 200 mL), and consequences of an interaction for different people taking the consumption of the fruit itself.5 The effect on drug same drug.2 Thus, it is probably wise to prescribe an alternative pharmacokinetics seems to be greater with regular consumption.
drug that is not affected by grapefruit juice consumption.
The clinical consequences can vary from an asymptomatic The table lists the commonly used drugs that are affected by increase in drug concentrations to life threatening events.2 5 Such grapefruit juice, but many other drugs can also be affected.
a life threatening event is described in a case report of impaired Further information can be obtained from other sources such as metabolism of amiodarone after ingestion of grapefruit juice the British National Formulary (appendix 1). More research is that led to an increase in QT interval and torsades de pointes.6 needed to define which other drugs currently on the market can Similarly, rhabdomyolysis has been described after co-ingestion be affected by grapefruit juice, and to develop better methods to assess the severity of the interaction for different people.
A second mechanism involves the inhibition of a member of Efforts to reduce the furanocoumarin content of grapefruit juice the influx transporter protein family (organic anion transporter are also under way through crossbreeding,9 alternative polypeptide; OATP) by grapefruit.8 Flavonoids such as naringin processing techniques,10 and the use of edible fungi.11 and hesperidin have been implicated in the mechanism of OATP Finally, although this editorial has focused on grapefruit juice, inhibition. The net effect is reduced bioavailability of the drug, furanocoumarins are also present in Seville oranges and with a decrease in its systemic and tissue concentrations and pomelos. Furthermore, other fruits and juices, including thus a decrease in its efficacy. In contrast to the effect of cranberry, Goji berry, and apple, contain other active moieties grapefruit juice on CYP3A4, the inhibition of OATPs shows a that can affect different P450 isoforms and transporters and clear volume (dose)-response association, which is competitive interact with different drugs. It is therefore important to take a in nature, with inhibition lasting about four hours. Thus, a simple careful dietary history from patients and provide them with the For personal use only: See rights and repr BMJ 2013;346:f1 doi: 10.1136/bmj.f1 (Published 7 January 2013) relevant information to minimise the effects of these potentially Paine MF, Widmer WW, Hart HL, Pusek SN, Beavers KL, Criss AB, et al. A furanocoumarin-free grapefruit juice establishes furanocoumarins as the mediators of the grapefruit juice-felodipine interaction. Am J Clin Nutr 2006;83:1097-105.
Lown KS, Bailey DG, Fontana RJ, Janardan SK, Adair CH, Fortlage LA, et al. Grapefruit Competing interests: The author has completed the ICMJE uniform juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression. J Clin Invest 1997;99:2545-53.
Seden K, Dickinson L, Khoo S, Back D. Grapefruit-drug interactions. Drugs request from the corresponding author) and declares: no support from Agosti S, Casalino L, Bertero G, Barsotti A, Brunelli C, Morelloni S. A dangerous fruit any organisation for the submitted work; no financial relationships with juice. Am J Emerg Med 2012;30:248.e5-8.
any organisations that might have an interest in the submitted work in Mazokopakis EE. Unusual causes of rhabdomyolysis. Intern Med J 2008;38:364-7.
Dolton MJ, Roufogalis BD, McLachlan AJ. Fruit juices as perpetrators of drug interactions: the previous three years; no other relationships or activities that could the role of organic anion-transporting polypeptides. Clin Pharmacol Ther 2012;92:622-30.
appear to have influenced the submitted work.
Greenblatt DJ, Zhao Y, Hanley MJ, Chen C, Harmatz JS, Cancalon PF, et al.
Mechanism-based inhibition of human cytochrome P450-3A activity by grapefruit hybrids Provenance and peer review: Commissioned; not externally peer having low furanocoumarin content. Xenobiotica 2012;42:1163-9.
10 Cancalon PF, Barros SM, Haun C, Widmer WW. Effect of maturity, processing, and storage on the furanocoumarin composition of grapefruit and grapefruit juice. J Food Sci Bailey DG, Spence JD, Munoz C, Arnold JM. Interaction of citrus juices with felodipine 11 Myung K, Narciso JA, Manthey JA. Removal of furanocoumarins in grapefruit juice by and nifedipine. Lancet 1991;337:268-9.
edible fungi. J Agric Food Chem 2008;56:12064-8.
Bailey DG, Dresser G, Arnold JM. Grapefruit-medication interactions: Forbidden fruit or avoidable consequences? CMAJ 2012; published online 26 Nov.
Cite this as: BMJ 2013;346:f1 BMJ Publishing Group Ltd 2013 For personal use only: See rights and repr BMJ 2013;346:f1 doi: 10.1136/bmj.f1 (Published 7 January 2013) Table 1| Drug interactions with grapefruit juice2 8
Mechanism Site of action Protein affected
Mechanism of interaction Effects of interaction
Examples of drugs affected
Intestinal wall Inhibition of cytochrome Irreversible inhibition; metabolism; increased drug antiarrhythmics (amiodarone, propafenone, (verapamil, amlodipine, felodipine, nifedipine, nicardipine); drugs that act on the central nervous system (carbamazepine, pimozide, quetiapine, buspirone, triazolam); cytotoxics (nilotinib, sunitinib, lapatanib); immunosuppressants (ciclosporin, tacrolimus, sirolimus); statins Aliskiren, celiprolol, fexofenadine, talinolol For personal use only: See rights and repr

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