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Editorials

Drug-grapefruit juice interactions

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

Re: Drug-grapefruit juice interactions

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: No competing interests

24 August 2013
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