Грейпфру́т (Citrus paradisi)[1] — субтропическое вечнозелёное дерево рода цитрус семейства рутовых (Rutaceae), а также его плод, достигающий в диаметре 30-40 см.

Внешне грейпфрут схож с апельсином, но мякоть его кислее с привкусом горечи. Несмотря на это, в энциклопедиях он безоговорочно отнесен к диетическим плодам. Грейпфрут является, предположительно, результатом природной гибридизации апельсина (Citrus sinensis) и поме́ло (Citrus maxima). При этом, он гораздо ближе ко второму, чем к первому. Впоследствии на его основе были созданы танжело (гибрид Citrus paradisi x Citrus reticulata, 1905) и минеола (разновидность танжело, производное танжерина сорта Dancy и грейпфрута сорта Duncan, 1931).

Влияние на здоровье

Некоторые вещества, содержащиеся в грейпфруте, вступают в активное взаимодействие с определёнными лекарственными средствами. Особенно это касается содержащихся в нём нарингенина и бергамоттина, которые задерживают изоформ цитохрома P450 (CYP3A4) в печени. Поэтому имеет смысл осведомиться о возможном влиянии на организм компонентов грейпфрута во время приёма лекарств.

Грейпфрут содержит также антиоксиданты, которые снижают уровень холестерина и улучшают пропорцию содержащихся HDL— и LDL— липопротеидов. Таким образом, один грейпфрут в день способствует нормализации уровня холестерина в крови. Это является особенно важным для людей, страдающих ишемической болезнью сердца и болезнями кровообращения, для которых повышенный уровень холестерина является ещё одним фактором риска. Исследователи из Еврейского университета (Иерусалим) пришли в 2006 г. к выводу, что грейпфруты с «красной» мякотью содержат намного больше веществ, понижающих уровень холестерина, чем грейпфруты «жёлтых» сортов.

Утверждается, что экстракт семени грейпфрута обладает сильным противомикробным и противогрибковым действием. Тем не менее, это требует подтверждения более глубокими научными исследованиями.

В целом, не рекомендуется принимать грейпфрутовый сок с лекарствами, так как он повышает содержание действующего вещества в потоке крови и тем самым вызывает эффект передозировки.

Грейпфрут для похудания

Грейпфрут есть основной компонент так называемой грейпфрутовой диеты, направленной на ускорение обмена веществ и сжигания жировых отложений. Этому способствует нарингин, содержащийся в мякоти, который ускоряет процесс пищеварения. Он также регулирует вялость кишечника, стимулирует обмен веществ, приводя, тем самым, к потере излишнего веса.

В 2004 г. стало известно, что грейпфрут может помочь не только при похудении, но также и при диабете. Действие основывается на том, что употребление грейпфрута способствует улучшению обмена сахаросодержащих веществ. Следовательно, понижается уровень содержания сахара в крови и уменьшается необходимость в инсулине.

Management of Grapefruit-Drug Interactions

AMY L. STUMP, PHARM.D., University of Alabama School of Medicine, Tuscaloosa, Alabama

TERRI MAYO, PHARM.D., DCH Regional Medical Center, Tuscaloosa, Alabama

ALAN BLUM, M.D., University of Alabama School of Medicine, Tuscaloosa, Alabama

Patient information: A handout on medicine interactions with grapefruit, written by the authors of this article, is provided on page 611.
A PDF version of this document is available. Download PDF now (4 pages /105 KB).

Grapefruit is a healthy addition to a well-balanced diet. However, the fruit has been shown to affect the metabolism of many medications, increasing the risk of toxicity and adverse effects. Characteristics of oral medications that may interact with grapefruit include extensive metabolism through the intestinal cytochrome P450 3A4 system, low bioavailability, and a narrow therapeutic index. Prominent medications known to interact with grapefruit include statins, antiarrhythmic agents, immunosuppressive agents, and calcium channel blockers. There are equally effective alternatives to these drug classes that do not have the potential to interact with grapefruit. These alternative drugs may be substituted if a patient experiences or is at risk of a grapefruit-drug interaction. Patients also may choose to exclude grapefruit from their diets and consume other fruits, including other types of citrus, to avoid an interaction. (Am Fam Physician 2006;74:605-8, 611. Copyright © 2006 American Academy of Family Physicians.)

Grapefruit is a citrus fruit that is low in calories; rich in vitamin C, potassium, and dietary fiber; and has been a recommended fruit of the American Heart Association's "Healthy Heart Campaign."1 The authors of a study2 that used grapefruit juice to mask the taste of ethanol inadvertently discovered an interaction between grapefruit and the calcium channel blocker felodipine (Plendil). They observed that patients who consumed grapefruit juice had felodipine plasma concentrations two to three times higher than normal levels.2

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendation
Evidence rating
References
Comments

Patients should discontinue grapefruit consumption for 72 hours before use
of a drug that may interact with it.
C
5, 6
The potential for a grapefruit-drug interaction persists for up to 72 hours according to one study.5

Potential grapefruit-drug interactions cannot be avoided by separating times of medication administration and grapefruit consumption.
C
5, 6
Studies have shown that consuming 8 oz of grapefruit juice may decrease the concentration of intestinal cytochrome P450 3A4 by 47 percent for 24 to 72 hours.

--------------------------------------------------------------------------------

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, see page 542 or http://www.aafp.org/afpsort.xml.

The discovery of this and other clinically significant interactions may have caused health care professionals to hesitate before universally recommending grapefruit as part of a healthy diet. Because grapefruit-drug interactions exist, strategies should be devised to manage potential interactions. A patient may choose to exclude grapefruit from his or her diet and substitute other fruits, including any other citrus.3 However, if the patient wishes to continue to consume grapefruit products, an alternate medication that does not have the potential to interact with grapefruit may be prescribed.

Mechanism of Interaction

The characteristics of medications that interact with grapefruit are well defined. The most significant of these characteristics is metabolism by the intestinal cytochrome P450 3A4 (CYP 3A4) system. CYP 3A4 is found in the liver and intestinal tract. Intestinal CYP 3A4 concentration can be decreased by 47 percent within four hours of grapefruit consumption.4 One study5 has shown that the interaction persists for up to 72 hours; therefore, it would be prudent to avoid grapefruit products for 72 hours before taking a medication with which they may interact.

Another study6 reported that consuming 8 oz of grapefruit juice can inhibit intestinal CYP 3A4 concentration for 24 to 72 hours. Therefore, separating the times of medication administration and grapefruit consumption is not a plausible solution.5,6 It is important to note that because of genetic polymorphism, persons have varying amounts of intestinal CYP 3A4; consequently, the extent of an interaction is not predictable from patient to patient.7,8

The substance or substances in grapefruit that inhibit intestinal CYP 3A4 have not been identified. In addition, grapefruit may decrease the intestinal transport of drugs into the circulation.7 Because intestinal CYP 3A4 is affected, the interaction will only occur with oral formulations. Studies of the intravenous form of drugs that are substrates of hepatic CYP 3A4 and have the potential to interact with grapefruit failed to demonstrate any effect on plasma concentration.4

Medications metabolized by intestinal CYP 3A4 that have a low oral bioavailability or a narrow therapeutic index are more likely to have clinically significant interactions with grapefruit products.9 Because medications metabolized extensively by intestinal CYP 3A4 generally have low oral bioavailability, and because grapefruit inhibits this metabolic pathway, higher plasma concentrations of these medications will result. Furthermore, if the medication has a narrow therapeutic index, small increases in plasma concentration may cause drastic increases in therapeutic or adverse effects.9

Management

When considering how to manage grapefruit-drug interactions, a physician should first decide if the interaction is clinically relevant. A number of medications (e.g., angiotensin receptor blockers, buspirone [BuSpar], estrogens, fexofenadine [Allegra], itraconazole [Sporanox], sildenafil [Viagra], triazolam [Halcion], warfarin [Coumadin]) reportedly or theoretically interact with grapefruit. However, many of these interactions have not been proven clinically significant, or inconsistent data exist.10-18 Table 19,19-30 describes medication classes that have had documented, clinically significant interactions with grapefruit products, and possible alternative therapies for these drugs.

table 1

Grapefruit-Drug Interactions and Alternative Therapies

Drug class
Drugs potentially affected by grapefruit
Effects of interaction
Alternative treatments

Antiarrhythmics
Amiodarone (Cordarone), disopyramide (Norpace), quinidine
Increased plasma concentrations of amiodarone may cause thyroid or pulmonary toxicity, liver injury, QTc prolongation, proarrhythmic disorders, and bradycardia.19

Increased plasma concentration of quinidine and disopyramide may be cardiotoxic causing torsades de pointes.9,20
Digoxin (Lanoxin), diltiazem (Cardizem), verapamil (Calan)

Beta blockers

Calcium channel blockers
Felodipine (Plendil), nicardipine (Cardene), nifedipine (Procardia), nimodipine (Nimotop), nisoldipine (Sular)
Increased plasma concentration may lead to flushing, peripheral edema, headaches, tachycardia, symptomatic hypotension, and myocardial infarction in rare cases.9
Amlodipine (Norvasc), diltiazem (Cardizem), verapamil (Calan)

Statins
Atorvastatin (Lipitor), lovastatin (Mevacor), simvastatin (Zocor)
Increased plasma concentration may cause headaches, gastrointestinal complaints, hepatic inflammation, and myopathies (e.g., rhabdomyolysis).21-24
Fluvastatin (Lescol), pravastatin (Pravachol), rosuvastatin (Crestor)

Fibric acids, nicotinic acid, or bile acid sequestrants

Immunosuppressants
Cyclosporine (Sandimmune, Neoral), tacrolimus (Prograf)
Increased drug exposure without effects on peak concentration may cause increased adverse events or toxicity evidenced by renal toxicity, hepatic toxicity, and increased immunosuppression.25-29
No alternatives available

Protease inhibitors
Saquinavir (Fortovase)
Increased plasma concentrations may cause increased side effects such as headache, fatigue, insomnia, and anxiety.30
Amprenavir (Agenerase), atazanavir (Reyataz), fosamprenavir (Lexiva), indinavir (Crixivan), lopinavir/ritonavir (Kaletra), nelfinavir (Viracept), ritonavir (Norvir)

--------------------------------------------------------------------------------

Information from references 9 and 19 through 30.

The importance of clearly understanding possible interactions between drugs and grapefruit products is becoming more evident. The manufacturers of cyclosporine (Sandimmune, Neoral) and simvastatin (Zocor) have gone so far as to place warnings on their drugs' package inserts.25,31,32

Members of various family medicine departments develop articles for "Clinical Pharmacology." This is one in a series coordinated by Allen F. Shaughnessy, Pharm.D., and Andrea E. Gordon, M.D., Tufts University Family Medicine Residency, Malden, Mass.

--------------------------------------------------------------------------------

The Authors

AMY L. STUMP, Pharm.D., is assistant clinical professor of pharmacy practice at the Auburn (Ala.) University Harrison School of Pharmacy Department of Pharmacy Practice. She also is assistant clinical professor of rural medicine in the University of Alabama School of Medicine Department of Community and Rural Medicine and the Institute for Rural Health Research, Tuscaloosa. Dr. Stump received her pharmacy degree from the University of Nebraska Medical Center College of Pharmacy, Omaha, and completed a primary care specialty pharmacy residency at Mission Hospitals/Mountain Area Health Education Center in Asheville, N.C.

TERRI MAYO, Pharm.D., is completing a drug information specialty pharmacy residency at DCH Regional Medical Center in Tuscaloosa, Ala. She received her pharmacy degree from the Auburn University Harrison School of Pharmacy.

ALAN BLUM, M.D., is professor and holds the Gerald Leon Wallace endowed chair in family medicine at the University of Alabama School of Medicine. He also is director of the university's Center for the Study of Tobacco and Society. Dr. Blum received his medical degree from the Emory University School of Medicine, Atlanta, Ga., and completed a family medicine residency at the University of Miami (Fla.).

Address correspondence to Alan Blum, M.D., 26 Pinehurst Dr., Tuscaloosa, AL 35401 (e-mail: ablum@cchs.ua.edu ). Reprints are not available from the authors.

Author disclosure: Nothing to disclose.

REFERENCES

1. American Heart Association. Learn and live. Delicious decisions. Accessed April 12, 2006, at: http://www.deliciousdecisions.org.

2. Bailey DG, Spence JD, Edgar B, Bayliff CD, Arnold JM. Ethanol enhances the hemodynamic effects of felodipine. Clin Invest Med 1989;12:357-62.

3. Bailey DG, Dresser GK, Kreeft JH, Munoz C, Freeman DJ, Bend JR. Grapefruit-felodipine interaction: effect of unprocessed fruit and probable active ingredients. Clin Pharmacol Ther 2000;68:468-77.

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

5. 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.

6. 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 subjects. Eur J Clin Pharmacol 1995;49:61-7.

7. Dresser GK, Bailey DG. The effects of fruit juices on drug disposition: a new model for drug interactions. Eur J Clin Invest 2003;33(suppl 2):10-6.

8. 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, U.S. Food and Drug Administration. Drug interactions with herbal products and grapefruit juice: a conference report. Clin Pharmacol Ther 2004;75:1-12.

9. Bailey DG, Dresser GK. Interactions between grapefruit juice and cardiovascular drugs. Am J Cardiovasc Drugs 2004;4:281-97.

10. Hukkinen SK, Varhe A, Olkkola KT, Neuvonen PJ. Plasma concentrations of triazolam are increased by concomitant ingestion of grapefruit juice. Clin Pharmacol Ther 1995;58:127-31.

11. Vanakoski J, Mattila MJ, Seppala T. Grapefruit juice does not enhance the effects of midazolam and triazolam in man. Eur J Clin Pharmacol 1996;50:501-8.

12. Lilja JJ, Kivisto KT, Backman JT, Neuvonen PJ. Effect of grapefruit juice dose on grapefruit juice-triazolam interaction: repeated consumption prolongs triazolam half-life. Eur J Clin Pharmacol 2000;56:411-5.

13. Lilja JJ, Kivisto KT, Backman JT, Lamberg TS, Neuvonen PJ. Grapefruit juice substantially increases plasma concentrations of buspirone. Clin Pharmacol Ther 1998;64:655-60.

14. Johnson MD, Newkirk G, White JR Jr. Clinically significant drug interactions. Postgrad Med 1999;105:193-206.

15. Garg SK, Kumar N, Bhargava VK, Prabhakar SK. Effect of grapefruit juice on carbamazepine bioavailability in patients with epilepsy. Clin Pharmacol Ther 1998;64:286-8.

16. Dresser GK, Kim RB, Bailey DG. Effect of grapefruit juice volume on the reduction of fexofenadine bioavailability: possible role of organic anion transporting polypeptides. Clin Pharmacol Ther 2005;77:170-7.

17. Gubbins PO, McConnell SA, Gurley BJ, Fincher TK, Franks AM, Williams DK, et al. Influence of grapefruit juice on the systemic availability of itraconazole oral solution in healthy adult volunteers. Pharmacotherapy 2004;24:460-7.

18. Zaidenstein R, Soback S, Gips M, Avni B, Dishi V, Weissgarten Y, et al. Effect of grapefruit juice on the pharmacokinetics of losartan and its active metabolite E3174 in healthy volunteers. Ther Drug Monit 2001;23:369-73.

19. Libersa CC, Brique SA, Motte KB, Caron JF, Guedon-Moreau LM, Humbert L, et al. Dramatic inhibition of amiodarone metabolism induced by grapefruit juice. Br J Clin Pharmacol 2000;49:373-8.

20. Min DI, Ku YM, Geraets DR, Lee H. Effect of grapefruit juice on the pharmacokinetics and pharmacodynamics of quinidine in healthy volunteers. J Clin Pharmacol 1996;36:469-76.

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

22. Lilja JJ, Neuvonen M, Neuvonen PJ. Effects of regular consumption of grapefruit juice on the pharmacokinetics of simvastatin. Br J Clin Pharmacol 2004;58:56-60.

23. 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.

24. 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;57:448-55.

25. Neoral soft gelatin capsules (cyclosporin capsules, USP) modified. Neoral oral solution (cyclosporin oral solution, USP) modified. Product information. East Hanover, N.J.: Novartis. March 2004. Accessed April 14, 2006 at: http://www.pharma.us.novartis.com/product/pi/pdf/neoral.pdf.

26. Min DI, Ku Y, Perry PJ, Ukah FO, Ashton K, Martin MF, et al. Effect of grapefruit juice on cyclosporine pharmacokinetics in renal transplant patients. Transplantation 1996;62:123-5.

27. Yee GC, Stanley DL, Pessa LJ, Dalla Costa T, Beltz SE, Ruiz J, et al. Effect of grapefruit juice on blood cyclosporin concentration. Lancet 1995;345:955-6.

28. Bistrup C, Nielsen FT, Jeppesen UE, Dieperink H. Effect of grapefruit juice on Sandimmune Neoral absorption among stable renal allograft recipients. Nephrol Dial Transplant 2001;16:373-7.

29. Kane GC, Lipsky JJ. Drug-grapefruit juice interactions. Mayo Clin Proc 2000;75:933-42.

30. Eagling VA, Profit L, Back DJ. Inhibition of the CYP3A4-mediated metabolism and P-glycoprotein-mediated transport of the HIV-1 protease inhibitor saquinavir by grapefruit juice components. Br J Clin Pharmacol 1999;48:543-52.

31. Sandimmune soft gelatin capsules (cyclosporin capsules, USP). Sandimmune oral solution (cyclosporin oral solution, USP). Sandimmune injection (cyclosporin injection, USP). Product information. East Hanover, N.J. Novartis. August 2005. Accessed July 18, 2006, at: http://www.pharma.us.novartis.com/product/pi/pdf/sandimmune.pdf

32. Tablets. Zocor (simvastatin). Product information. Whitehouse Station, N.J.: Merck and Co., Inc. November 2004. Accessed April 14, 2006 at: http://www.zocor.com/zocor/shared/documents/english/pi.pdf.

--------------------------------------------------------------------------------

Copyright © 2006 by the American Academy of Family Physicians.