Editorials

Drug-grapefruit juice interactions

BMJ 2013; 346 doi: http://dx.doi.org/10.1136/bmj.f1 (Published 07 January 2013) Cite this as: BMJ 2013;346:f1

Re: Drug-grapefruit juice interactions

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: No competing interests

25 January 2013
Warren D Backman
Final year medical student
Dr Ameet Bakhai
University College London
Gower Street, London, WC1E 6BT
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