Drug-grapefruit juice interactions

BMJ 2013; 346 doi: http://dx.doi.org/10.1136/bmj.f1 (Published 7 January 2013)
Cite this as: BMJ 2013;346:f1

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The debate on grapefruit-drug interactions (GFJ-DI) appearing in your recent issues 2 3 refers. GFJ-DI have been documented in over 225 publications in the scientific literature4 5 6 (table 1).

GFJ-DI only affect orally but not parenterally administered drugs. Since both P-glycoprotein (P-gp) and CYP3A4 act synergistically as barriers to systemic absorption of drugs while organic anion transporter protein (OATP) facilitates intestinal drug absorption, concurrent inhibition of these proteins would have opposing effects on drug bioavailability (table 1). GFJ-DI are therefore complex and difficult to predict.
Consequently, clinical manifestations of GFJ-DI are often inconsistent and misunderstood. However, the few life-threatening clinical cases so far reported appear to have one common dominator: the patients have been taking large quantities of the grapefruit juice. In the case cited by Professor Pirmohamed1 7, for example, the patient presented with a prolonged QT interval associated with ventricular arrhythmias including torsades des pointes after she had been drinking large quantities of grapefruit juice. What was overlooked, however, was that grapefruit juice also contains significantly large amounts of naringin that gets hydrolysed by intestinal bacterial metabolism upon ingestion to its aglycone, naringenin which is known to prolong QTC by inhibiting rapid component of delayed rectifier K+ (IKr) component in healthy subjects and in patients with dilated or hypertensive cardiomyopathy 9. So, torsades des pointes could have also been a consequence of direct naringenin effect on the myocardium as opposed to grapefruit juice-amiodarone interaction. Drugs with narrow therapeutic index and are also substrates of CYP3A4 such as warfarin would be expected to be more prone to GFJ-DI but so far no clinically significant cases have been documented.
I therefore concur with Backman and Bakhai2 that potential dangers of GFJ-DI are largely exaggerated. We and others 10 11 12 13 have previously reported antidiabetic and anti-dyslipidemic effects of the grapefruit juice and its bioactive flavonoids and argue that unwarranted scare mongering on the dangers of GFJ-DI without substantial clinical evidence would otherwise deny such patients potentially therapeutic benefits that they richly deserve. Lack of or sparseness of anecdotal evidence on clinically relevant GFJ-DI is surely proof enough of the diminished magnitude of the inherent risks. Patients’ dietary habits need to be recorded in clinical notes and where risks of adverse effects are evidenced, patients may be shifted to alternative medications within the same category or put on parenteral drug administration, where appropriate.

Competing interests: None declared.

References

1. Pirmohamed M. Drug-grapefruit juice interactions: two mechanisms are clear but individual responses vary. BMJ 2013 Jan 7;346:f1. doi: 10.1136/bmj.f1
2. Backman WD, Bakhai A. A more balanced approach to drug-grapefruit juice interactions. BMJ. 2013 Feb 26;346:f1073. doi: 10.1136/bmj.f1073.
3. Pirmohamed M. Drug-grapefruit juice interactions: two mechanisms are clear but individual responses vary. BMJ. 2013 Jan 7;346:f1. doi: 10.1136/bmj.f1.
4. Greenblatt DJ, Patki KC, von Moltke LL, Shader RI. Drug interactions with grapefruit juice: an update. J Clin Pyschopharmacol 2001; 21:357–359.
5. Bailey DG, Dresser G, Arnold JM. Grapefruit-medication interactions: Forbidden fruit or avoidable consequences? CMAJ 2012.
6. Seden K, Dickinson L, Khoo S, Back D. Grapefruit-drug interactions. Drugs. 2010 Dec 24;70(18):2373-407.
7. Agosti S, Casalino L, Bertero G, Barsotti A, Brunelli C, Morelloni S. A dangerous fruit juice. Am J Emerg Med 2012;30:248.e5-8.
8. Piccirillo G, Magrì D, Matera S, Magnanti M, Pasquazzi E, Schifano E, Velitti S, Mitra M, Marigliano V, Paroli M, Ghiselli A. Effects of pink grapefruit juice on QT variability in patients with dilated or hypertensive cardiomyopathy and in healthy subjects. Transl Res. 2008 May;151(5):267-72.
9. Owira PM, Ojewole JA. The grapefruit: an old wine in a new glass? Metabolic and cardiovascular perspectives. Cardiovasc J Afr. 2010 Sep-Oct;21(5):280-5.
10. Owira PM, Ojewole JA. Grapefruit juice improves glycemic control but exacerbates metformin-induced lactic acidosis in non-diabetic rats. Methods Find Exp Clin Pharmacol. 2009 Nov;31(9):563-70.
11. Xulu S, Oroma Owira PM. Naringin ameliorates atherogenic dyslipidemia but not hyperglycemia in rats with type 1 diabetes. J Cardiovasc Pharmacol. 2012 Feb;59(2):133-41.
12. Fujioka K, Greenway F, Sheard J, Ying Y. The effects of grapefruit on weight and insulin resistance: relationship to the metabolic syndrome. J Med Food. 2006 Spring;9(1):49-54.

Competing interests: None declared

Peter Owira, Clinical Pharmacologist

University of Kwazulu-Natala, Department of Pharmacology, Discipline of Pharmaceutical Sciences, School of Health Sciences, University of KwaZulu-Natal, Private Bag X54001, Durban 4000, South Africa

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Backman and Bakhai question the clinical importance of drug-grapefruit juice interactions, focusing on statins. The risk of statin-related myopathy is concentration-dependent, but not everybody who has the same (high) plasma statin concentration will develop muscle injury (because susceptibility varies)1.

However, one cannot conclude that this risk is absent based on anecdotal evidence or the sparseness of case reports. Frankly, drug histories are poorly documented in case-notes, and direct questioning of dietary habits is virtually non-existent. Thus, we have no data on either the numerator (patients with statin myopathy while taking grapefruit juice) or denominator (all patients who consume grapefruit juice while on statins). There is also significant under-reporting of serious adverse reactions, reflected by the fact that there are only 4 reports of an interaction between simvastatin and grapefruit juice on the Yellow Card database (M Foy, MHRA, personal communication, Feb 2013).

Moreover, 200ml of grapefruit juice can increase the kinetic parameters of 40mg simvastatin between 3.3-4.3 fold2. Given the dose proportionality of simvastatin pharmacokinetics, an increase in its dose from 40mg to 80mg/day leads to doubling of the kinetic parameters. We now rarely use 80mg/day simvastatin because of the risk of muscle injury, and so why should we have different rules for the interaction between grapefruit juice and simvastatin?

To conclude, we can neither predict who will develop statin myopathy, nor quantify the risk in patients who drink grapefruit juice. Thus, I would stand by my recommendation to avoid grapefruit juice in patients who take simvastatin or atorvastatin. Of course, there are statins (e.g. rosuvastatin and pravastatin) which do not interact with grapefruit juice providing an option for patients who do not want to change their dietary habits.

Finally, other fruit juices, which do not interact with CYP3A4-metabolised drugs are likely to have health benefits similar to those of grapefruit juice.

1. Link E, Parish S, Armitage J, Bowman L, Heath S, et al. SLCO1B1 variants and statin-induced myopathy--a genomewide study. N Engl J Med 2008;359(8):789-99.
2. Lilja JJ, Neuvonen M, Neuvonen PJ. Effects of regular consumption of grapefruit juice on the pharmacokinetics of simvastatin. Br J Clin Pharmacol 2004;58(1):56-60.

Competing interests: None declared

Munir Pirmohamed, Professor of Clinical Pharmacology

The University of Liverpool, Wolfson Centre for Personalised Medicine, 1-5 Brownlow Street, Liverpool, L3 5TY

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28 January 2013

Pirmohamed describes in depth the theoretical interactions between Statin and grapefruit juice. But he states that the interactions are difficult to quantify or predict and fails to give any absolute measure of risks. He suggests that if the Cytochrome metabolism is irreversibly poisoned by grapefruit, than statin levels might be increased a thousand-fold.

Backman, Bakhai, and McDaid have expertly shown these risks to be rare or unmeasurable in reality.

So rather than denigrate GFJ , why not turn threat into opportunity and advocate a 'polyjuice' approach - a new health drink - Grapefruit juice with a 10 microgramme dash of statin.

Can our Professor of Pharmacology, in the interest of Translational Medicine, develop a range of concentrations - and test the product in a wide range of settings - for safety and efficacy. It is obviously so cheap and acceptable it could save the NHS millions.

I waive any rights to patent or royalties.

Competing interests: None declared

L Sam Lewis, GP Trainer

Newport Surgery, Surgery, Newport, Pembrokeshire SA42 0TJ

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I've always wondered about the science behind why Grapefruit Juice was to be avoided when using Simvastatin. So it was useful to read the editorial from Professor Munir Pirmohamed.

This focuses on the mechanisms but gives no insight that is particularly useful when talking with patients. Simvastatin has a proven track record in primary and secondayr prevention through multiple trials. WHenever cosiderig a Statin in Primary prevention following QRisk Assessmnet, as part of informed choice I discuss both relative percentage reduction in Risk and Absolute numbers needed to treat to prevent a Cardiovascular event.

With the theoretical risks for mixing Grapefruit and Simvastatin (and the other drugs listed) I do not have information on relative risk of harm or absolute numbers needed to harm from the GFJ+Drug combaintions.

The rapid response from BakMan and Bakhai (A local cardiologist to me) helps. GFJ has its own benefits. Numbers neeeded to Harm from the experience they report over 10 years seems so high they have not been able to establish.

In practice what does this mean for me?
If patients have been on simvastatin for a long time I do not feel I would be able to persuade them to change to another Statin based on the available information. Even more so if they are on Atorvastatin.

If they do want to change then pravastatin will be my first (most cost efective) recomendation.

If they are on Simvastatin/Atorvastatin and ask whehter they can drink GFJ I will say their are theoretical risks though the experience of at least one of our local Cardiologists and their colleagues is that they are not aware of anyone coming to any harm over the last 10 years.

Any pragmatic improvements on this approach would be appreciated.

It is reassuring to see the response from

Competing interests: None declared

Patrick McDaid, GP

Heahtfielde Medical Centre, 8 Lyttelton Road Hampstead Garden Suburbs London N2 0EQ

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In a recent editorial 1, Prof Pirmohamed provided a concise update on the interactions between grapefruit juice (GFJ) and various drugs. It focused significantly on “severe, sometimes fatal, interactions” and was based on pharmacology and case reports. The numerous health benefits of GFJ were not described, nor was the rarity of clinically significant GFJ-drug interactions. This picture is rather biased and adds to the burden of fear that GFJ and drug interactions have attracted amongst healthcare providers and patients alike.

GFJ is rich in flavonoids, that have a preventive influence on many chronic diseases 2, but this fact is overshadowed by the possible risk of interactions between drugs and GFJ. When prescribing statins for example, primary care colleagues are commonly taught to advise patients to completely remove the fruit and the juice from their diet. In some cases this may be a barrier to concordance with the recommended therapy.

In our experience, and in that of our experienced colleagues, we have yet to come across clinically meaningful interactions of drugs and GFJ. This is despite our day to day experience of managing patients on statins, calcium channel antagonists, anti-platelet agents and anti-arrhythmics, which covers over 10,000 patients in the last 10 years alone. Likewise, there is little formal evidence of an impact, even from large scale clinical trials, with adjudicated and well documented endpoints.

This negative slant on GFJ—particularly in the context of statin therapy—has led us to detail some of the key publications, which span the last 13 years, in an attempt to better balance the editorial and enable appropriate discussion with patients.

GFJ has been shown experimentally to decrease the pre-systemic metabolism of simvastatin and atorvastatin, thus increasing drug bioavailability. As such, the British National Formulary (BNF) cites an interaction between grapefruit juice and these two drugs. To this end, it is important to confirm and reiterate that there is no contraindication to GFJ consumption in those taking pravastatin, fluvastatin or rosuvastatin. Furthermore, the BNF considers only simvastatin—not atorvastatin—to have a “potentially serious” interaction with grapefruit juice.

The key literature regarding simvastatin is as follows. In a Finnish study 3, healthy volunteers consumed multiple daily doses of double-strength GFJ prior to and on the day of taking a first dose of 60mg simvastatin (cf. starting dose of 10-40mg in BNF). Although the authors measured increases in plasma levels of simvastatin and its active metabolites, they did not report any adverse effects. Secondly, as Reamy and Stephens helpfully pointed out 4, the subjects were drinking the equivalent of 1.2 litres of regular strength GFJ per day, an excessive amount even for grapefruit enthusiasts. The same Finnish authors conducted a follow-up study which showed that the effect of GFJ consumption at 24 hours post-statin dose is only 10% of its effect when taken concomitantly 5. Other experiments with lovastatin, a drug which pharmacologically resembles simvastatin, have also been conducted with similar findings 6-7. There is only one case report of GFJ-related rhabdomyolysis in a patient taking simvastatin, specifically 80 mg daily 8, a dose which is now out of favour. So for simvastatin, which has been prescribed to millions of people with dyslipidaemia, there are surprisingly few published data to support a clinically significant, common adverse effect induced by GFJ. If one is to agree with us that the evidence for a serious GFJ-simvastatin interaction is scant, then by corollary the evidence for atorvastatin is even more scant9-12.

In summary, while there are clearly some articles documenting concerning interactions between GFJ and drugs in some patients, millions of other patients are consuming these drugs, often with GFJ, without adverse effects. The interaction is therefore not only unpredictable in individuals but may have little clinical relevance. This includes the case of statins too, unless the juice is being consumed in high concentrations daily. GFJ has many potential anti-oxidant effects which are likely to benefit patients, and therefore a more balanced and considerate approach to the discussion of healthy natural products and drug interactions is warranted between physician and patient.

Correspondence to Dr Ameet Bakhai, Consultant Cardiologist, Barnet & Chase Farm Hospitals NHS Trust, abakhai@nhs.net

References
1. Pirmohamed M. Drug-grapefruit juice interactions. BMJ 2013;346:f1.
2. Mertens-Talcott SU, Zadezensky I, De Castro WV, Derendorf H, Butterweck V. Grapefruit-drug interactions: can interactions with drugs be avoided? J Clin Pharmacol 2006;46(12):1390-416.
3. Lilja JJ, Kivisto KT, Neuvonen PJ. Grapefruit juice-simvastatin interaction: effect on serum concentrations of simvastatin, simvastatin acid, and HMG-CoA reductase inhibitors. Clin Pharmacol Ther 1998;64(5):477-83.
4. Reamy BV, Stephens MB. The grapefruit-drug interaction debate: role of statins. Am Fam Physician 2007;76(2):190, 92; author reply 92.
5. Lilja JJ, Kivisto KT, Neuvonen PJ. Duration of effect of grapefruit juice on the pharmacokinetics of the CYP3A4 substrate simvastatin. Clin Pharmacol Ther 2000;68(4):384-90.
6. Kantola T, Kivisto KT, Neuvonen PJ. Grapefruit juice greatly increases serum concentrations of lovastatin and lovastatin acid. Clin Pharmacol Ther 1998;63(4):397-402.
7. Rogers JD, Zhao J, Liu L, Amin RD, Gagliano KD, Porras AG, et al. Grapefruit juice has minimal effects on plasma concentrations of lovastatin-derived 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Clin Pharmacol Ther 1999;66(4):358-66.
8. Dreier JP, Endres M. Statin-associated rhabdomyolysis triggered by grapefruit consumption. Neurology 2004;62(4):670.
9. Lilja JJ, Kivisto KT, Neuvonen PJ. Grapefruit juice increases serum concentrations of atorvastatin and has no effect on pravastatin. Clin Pharmacol Ther 1999;66(2):118-27.
10. Fukazawa I, Uchida N, Uchida E, Yasuhara H. Effects of grapefruit juice on pharmacokinetics of atorvastatin and pravastatin in Japanese. Br J Clin Pharmacol 2004;57(4):448-55.
11. Reddy P, Ellington D, Zhu Y, Zdrojewski I, Parent SJ, Harmatz JS, et al. Serum concentrations and clinical effects of atorvastatin in patients taking grapefruit juice daily. Br J Clin Pharmacol 2011;72(3):434-41.
12. Mazokopakis EE. Unusual causes of rhabdomyolysis. Intern Med J 2008;38(5):364-7.

Competing interests: None declared

Warren D Backman, Final year medical student

Dr Ameet Bakhai

University College London , Gower Street, London, WC1E 6BT

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