Letters to the Editor

The Grapefruit-Drug Interaction Debate: Role of Statins



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Am Fam Physician. 2007 Jul 15;76(2):190-192.

to the editor: We would like to raise several concerns we have with the article, “Management of Grapefruit-Drug Interactions,”1 which provided a relatively concise overview of this topic. Atherosclerotic vascular disease remains the leading cause of death in the United States. The use of statins for the primary and secondary prevention of atherosclerotic vascular disease has an extensive evidence base and has been proven repeatedly to reduce cardiac events and mortality. However, even in the best of circumstances, only 48 percent of patients for whom these medications are clinically indicated are receiving the recommended treatment for their hyperlipidemia. For patients taking statins, long-term medication adherence is a significant challenge for physicians.2 Our primary concern is that exaggerated statements about the clinical significance of grapefruit-statin interactions will further reduce the use of this important class of medications.

Most of the cited studies in the article's1 Table 13,4 come from a single Scandinavian laboratory and use doses of grapefruit juice that far exceed normal daily intake. These results are very difficult to generalize to typical patients seen by family physicians in the United States.

An additional, and perhaps more significant concern is that these studies demonstrated no clinical or patient-oriented outcomes; they merely reported increased serum concentrations of lovastatin (Mevacor) and simvastatin (Zocor). Whether there is a log-linear relationship between serum concentration and clinical morbidity is a matter of debate. The cited studies also used high-dose statins (80 mg of lovastatin, 60 mg of simvastatin) and unrealistically high volumes of grapefruit juice. Specifically, 200 mL of double-strength juice was consumed three times per day, which equates to 1,200 mL (40 oz) per day of regular-strength grapefruit juice. Even patients who enjoy grapefruit juice do not ingest more than one quart each day! Additionally, one study cited by the authors showed that when simvastatin was taken 24 hours after ingestion of the same large volume (1,200 mL) of grapefruit juice, the effect of grapefruit juice on the concentration of simvastatin was only 10 percent of that when the statin and juice were taken concomitantly.5

In contrast, another study not cited by the authors examined normal-dose lovastatin (40 mg) in patients who consumed a typical amount (8 oz daily) of grapefruit juice. This study showed “a minimal effect on plasma concentrations” of lovastatin and no deleterious clinical outcomes.6

Rather than dissuade patients from the healthful consumption of grapefruit juice or the use of statins, it would be better to tell patients taking these drugs that they may consume up to 8 oz of grapefruit juice in the morning. Secondly, they should be instructed to always take their statins in the evening. These measures help minimize any grapefruit-drug interaction and may also increase the potency of statins because all are more potent inhibitors of hepatic HMG CoA reductase inhibitors when taken at night.

Author disclosure: Nothing to disclose.

The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the U.S. Air Force Medical Department, the U.S. Navy Medical Corps, or the Air Force services or U.S. Navy at large.

REFERENCES

1. Stump AL, Mayo T, Blum A. Management of grapefruit-drug interactions. Am Fam Physician. 2006;74:605–8.

2. McGlynn EA, Asch SM, Adams J, Kessey J, Hicks J, DeCristofaro A, et al. The quality of health care delivered to adults in the United States. N Engl J Med. 2003;348:2635–45.

3. Kantola T, Kivisto KT, Neuvonen PJ. Grapefruit juice greatly increases serum concentrations of lovastatin and lovastatin acid. Clin Pharmacol Ther. 1998;63:397–402.

4. 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;64:477–83.

5. 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;66:358–66.

6. Lilja JJ, Kivisto KT, Neuvonen PJ. Duration of effect of grapefruit juice on the pharmacokinetics of the CYP3A4 substrate simvastatin. Clin Pharmacol Ther. 2000;68:384–90.

in reply: In writing our article, we sought to inform family physicians about medications that interact with grapefruit products and the alternative medications that can be used for those patients who wish to continue to use grapefruit as a part of a healthy lifestyle.1 Table 1 of our article, entitled “Grapefruit-Drug Interactions and Alternative Therapies,” was intended to provide a “quick-look” reference to alternative medications in each drug class in which there has been a report of grapefruit-drug interactions.

Drs. Reamy and Stephens are rightly concerned about the lack of clinical and patient-oriented outcomes regarding grapefruit interactions. We are also aware of this and consequently labeled our key recommendations for practice with a SORT evidence rating of C (consensus, disease-oriented evidence, usual practice, expert opinion, or case series). We also feel that the evidence reported in the literature is unclear in describing the magnitude and duration of the effect of grapefruit on the intestinal cytochrome P450 3A4 (CYP3A4) isoenzyme system. For example, one study has shown that intestinal CYP3A4 concentration can be decreased by 47 percent within four hours of grapefruit consumption.2 Another study demonstrated that the inhibition of CYP3A4 can persist for 24 to 72 hours,3 whereas Takanaga and colleagues have shown the interaction to persist for 72 hours.4 The effect of patient genetic polymorphism in relation to intestinal CYP3A4 concentration makes for an interaction that is highly difficult to predict from patient to patient regardless of the amount or concentration of grapefruit consumed.5,6

The choice of medication used when a patient wishes to consume grapefruit products should be carefully considered. In the case that Drs. Reamy and Stephens have posed involving the use of hepatic HMG CoA reductase inhibitors (statins), a patient who wishes to consume grapefruit could use fluvastatin (Lescol), pravastatin (Pravachol), or rosuvastatin (Crestor) without any potential for interaction, and therefore decrease the risk of potential adverse effects.1 If none of these alternatives is appropriate, then the physician must consider risk versus benefit in light of the available evidence and work with the patient in making the best decision regarding medication and lifestyle treatment of health conditions.

Author disclosure: Nothing to disclose.

REFERENCES

1. Stump AL, Mayo T, Blum A. Management of grapefruit-drug interactions. Am Fam Physician. 2006;74:605–8.

2. Takanaga H, Ohnishi A, Murakami H, Matsuo H, Higuchi S, Urae A, et al. Relationship between time after intake of grapefruit juice and the effect on pharmacokinetics and pharmacodynamics of nisoldipine in healthy subjects. Clin Pharmacol Ther. 2000;67:201–14.

3. Dahan A, Altman H. Food-drug interaction: grapefruit juice augments drug bioavailability-mechanism, extent and relevance. Eur J Clin Nutr. 2004;58:1–9.

4. Lundahl J, Regardh CG, Edgar B, Johnsson G. Relationship between time of intake of grapefruit juice and its effect on pharmacokinetics and pharmacodynamics of felodipine in healthy subject. Eur J Clin Pharmacol. 1995;49:61–7.

5. Dresser GK, Bailey DG. The effects of fruit juices on drug disposition: a new model for drug interactions. Eur J Clin Invest. 2003;33suppl 210–6.

6. Huang SM, Hall SD, Watkins P, Love LA, Serabjit-Singh C, Betz JM, et al., for the Center for Drug Evaluation and Research and Office of Regulatory Affairs, Food and Drug Administration. Drug interactions with herbal products and grapefruit juice: a conference report. Clin Pharmacol Ther. 2004;75:1–12.

Send letters to Kenneth W. Lin, MD, MPH, Associate Deputy Editor for AFP Online, e-mail: afplet@aafp.org, or 11400 Tomahawk Creek Pkwy., Leawood, KS 66211-2680.

Please include your complete address, e-mail address, and telephone number. Letters should be fewer than 400 words and limited to six references, one table or figure, and three authors.

Letters submitted for publication in AFP must not be submitted to any other publication. Possible conflicts of interest must be disclosed at time of submission. Submission of a letter will be construed as granting the American Academy of Family Physicians permission to publish the letter in any of its publications in any form. The editors may edit letters to meet style and space requirements.


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