jugo toronja
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CMAJ AUG. 6, 2002; 167 (3) 279
2002 Canadian Medical Association or its licensors
Engl J Med1994;331:315-7.8. Simor AE, Ofner-Agostini M, Bryce E, Green K, McGeer A, Mulvey M, et
al. The evolution of methicillin-resistant Staphylococcus aureus in Canadianhospitals: 5 years of national surveillance. CMAJ2001;165(1):21-6.
9. Sinclair A. Genetics 101: the polymerase chain reaction. CMAJ. In press.10. Armstrong K, Eisen A, Weber B. Assessing the risk of breast cancer.N Engl J
Med2000;342:564-71.11. Yan H, Kinzler KW, Vogelstein B. Genetic testing present and future. Sci-
ence 2000;289:1890-2.
12. Van Ommen GJ, Bakker E, den Dunnen JT. The human genome project andthe future of diagnostics, treatment and prevention. Lancet1999;354(Suppl1):S5-10.
13. Marx J. DNA arrays reveal cancer in its many forms. Science 2000;289:1670-2.14. Kurella M, Hsiao LL, Yoshida T, Randall JD, Chow G, Sarang SS, et al.
DNA microarray analysis of complex biologic processes. J Am Soc Nephrol2001;12:1072-8.
15. van Tilburg J, van Haeften TW, Pearson P, Wijmenga C. Defining the ge-netic contribution of type 2 diabetes mellitus.J Med Genet2001;38:569-78.
16. Sade W. Pharmacogenomics. BMJ1999;319:1286.17. Phillips KA, Veenstra DL, Oren E, Lee JK, Sade W. Potential role of phar-
macogenomics in reducing adverse drug reactions: a systematic review.JAMA2001;286(18):2270-9.
18. Hamels S, Gala JL, Dufour S, Vannuffel P, Zammatteo N, Remacle J. Con-sensus PCR and microarray for diagnosis of the genus Staphylococcus, species,and methicillin resistance. Biotechniques2001;31:1364-6,1368,1370-2.
19. Gingeras TR, Ghandour G, Wang E, Berno A, Small PM, Drobniewski F, etal. Simultaneous genotyping and species identification using hybridizationpattern recognition analysis of generic Mycobacterium DNA arrays. Genome
Res1998;8:435-48.20. Lytwyn A, Sellors JW, Mahony JB, Daya D, Chapman W, Ellis N, et al.
Comparison of human papillomavirus DNA testing and repeat Papanicolaou
test in women with low-grade cervical cytologic abnormalities: a randomizedtrial. CMAJ 2000;163(6):701-7.
21. Kulaga S, Behr M, Schwartzman K. Genetic fingerprinting in the study of tu-berculosis transmission. CMAJ1999;161(9):1165-9.
22. King HC, Animesh AS. Gene expression profile analysis by DNA microar-rays: promise and pitfalls.JAMA 2001;286:2280-8.
23. Aitman TJ. DNA microarrays in medical practice. BMJ2001;232:611-5.
Correspondence:Dr. Alison Sinclair, 406-337 St. James St.,Victoria BC V8V 1J7; fax 250 380-6717; [email protected]
Reason for posting:Grapefruit juice in-teracts with a number of medications.
Th is unusua l di scovery was madeserendipitously in 1989 during an ex-periment designed to test the effect ofethanol on a calcium-channel blocker.1
The observed response was later deter-mined to be due to the grapefruit juice
delivery vehicle rather than the alcohol.In the past decade, the list of drug in-teractions with grapefruit juice has ex-panded to include several classes ofmedication, precipitating a recent advi-sory from Health Canada.2
The interaction:As little as 250 mL ofgrapefruit juice can change the metabo-lism of some drugs.3This drugfood in-teraction occurs because of a commonpathway involving a specific isoform ofcytochrome P450 CYP3A4 pres-
ent in both the liver and the intestinalwall . Studies suggest that grapefruitjuice exerts its effect primarily at thelevel of the intestine.4
After ingestion, a substrate con-tained in the grapefruit binds to the in-testinal isoenzyme, impairing first-passmetabolism directly and causing a sus-tained decrease in CYP3A4 protein ex-pression.5 Within 4 hours of ingestion,a reduction in the effective CYP3A4
concentration occurs, with effects last-ing up to 24 hours.6 The net result isinhibition of drug metabolism in the in-testine and increased oral bioavailabil-ity. Because of the prolonged response,separating the intake of the drug andthe juice does not prevent interference.
Individuals express CYP3A4 in differ-
ent proportions, those with the highestintestinal concentration being most sus-ceptible to grapefruit juicedrug interac-tions.5 An effect is seen with the wholefruit as well as its juice, so caution shouldbe exercised with both.7 The precisechemical compound in grapefruit thatcauses the interaction has not been iden-tified. There is no similar reaction with
orange juice, although there is some sus-picion that sour oranges such as theSeville variety, may have some effect.8Arecent study, however, that tested theknown interference of grapefruit juice
with cyclosporine showed no similar ef-fect with Seville oranges.9
There is some interest in the poten-
tial therapeutic benefit of adding grape-fruit juice to a drug regimen to increaseoral bioavailability.3 The limitation isthe individual variation in patient re-sponse. However, if the chemical thatcauses grapefruits CYP3A4 inhibitionis elucidated, there may be an opportu-nity to modulate that pathway in a con-trolled fashion.
HE ALT H A ND
DR UG
AL E R TS
Grapefruit juice: potential drug interactions
Canadian Adverse Reaction NewsletterBulletin canadien des effets indsirables
To receive the Newsletter and health product Advisories by email,join Health Canadas Health_Prod_Info mailing list.
Go to www.hc-sc.gc.ca/hpb-dgps/therapeut/htmleng/adr.htmland click on "subscribe."
Inscrivez-vous la liste Info_Prod_Sant de Sant Canada pour recevoir parcourriel le Bulletin et les Avis au sujet des produits de sant. Rendez-vous ladressewww.hc-sc.gc.ca/hpb-dgps/therapeut/htmlfrn/adr.htmlet cliquez sur abonnement .
Report adverse reactions toll free to Health CanadaSignaler sans frais des effets indsirables Sant Canada
Tel./Tl. : 866 234-2345 Fax/Tlc. : 866 678-6789Email/Courriel: [email protected]
PR A C TI C E
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What to do:Much of the data obtainedon grapefruit juicedrug interactionsinvolved measuring serum drug con-centrations in small numbers of healthy
volunteers. Because of the limited dataand only occasional case reports,10 it isdifficult to quantify the clinical signifi-cance for individual patients. One mayassume that the interaction occurs pri-marily with oral medicines, and only
with those that share the CYP3A4
metabolism pathway, with the conse-quence being increased oral bioavail-ability, higher serum drug concentra-tions and associated adverse effects.
Physicians should review medicationlists often, with the goal of warning pa-tients about adverse interactions. A listof medicines with which patientsshould not consume grapefruit is pro-
vided in Table 1.3,11,12 In the case of sev-eral medications that share the
CYP3A4 metabolism pathway, but forwhich a clinical effect has not been elu-cidated or is theoretical, patients shouldbe advised to consume grapefruit cau-tiously and be monitored for toxicity.
James MaskalykEditorial Fellow, CMAJ
References1. Bailey DG, Spence JD, Edgar B, Bayliff CD,
Arnold JM. Ethanol enhances the hemodynamic ef-fects of felodipine. Clin Invest Med1989;12:357-62.
2. Health Canada is advising Canadians not to takecertain drugs with grapefruit juice. Ottawa:Health Canada; 2002 Jun 21. Available: www.hc-sc.gc.ca/english/protection/warnings/2002/2002_49e.htm (accessed 2002 Jul 9).
3. Kane G, Lipsky J. Druggrapefruit juice interac-tions.Mayo Clin Proc2000;75:933-42.
4. Lundahl J, Regardh CJ, Edgar B, Johnsson G.Effects of grapefruit juice ingestion pharma-cokinetics and haemodynamics of intravenouslyand orally administered felodipine in healthymen.Eur J Pharmacol1997;52:139-45.
5. Lown KS, Bailey DG, Fontana RJ, Janardan SK,Adair CH, Fort lage LA, et al. Grapefruit juiceincreases felodipine oral availability in humans
by decreasing intestinal CYP3A protein expres-sion.J Clin Invest1997;99(10):2545-53.
6. Lundahl J, Regardh CG, Edgar B, Johnsson G.Relationship between time of intake of grape-fruit juice and its effect on pharmacokinetics andpharmacodynamics of felodipine in healthy sub-
jects.Eur J Clin Pharmacol1995;49:61-7.7. Bailey DG, Kreeft JH, Munoz C, Freeman DJ,
Bend JR. Grapefruit juicefelodipine interaction:effect of segments and an extract from unprocessedfruits [abstract]. Clin Pharmacol Ther2000;67:107.
8. Malhotra S, Bailey DG, Paine MF, Watkins PBSeville orange juicefelodipine interaction: com-parison with dilute grapefruit juice and involve-ment of furocoumarins. Clin Pharmacol Ther2001;69(1):14-23.
9. Edwards DJ, Fitzsimmons ME, Schuetz EG, Ya-
suda K, Ducharme MP, Warbasse LH, et al.6,7-Dihydrobergamottin in grapefruit juice andSeville orange juice: effects on cyclosporine dis-position, enterocyte CYP3A4, and P-glycopro-tein. Clin Pharmacol Ther1999;65:237-44.
10. Goldbart A, Press J, Sofer S, Kapelushnik J. Nearfatal acute colchicine intoxication in a child. Acase report.Eur J Pediatr2000;159(12):895-7.
11. Drug administration and grapefruit juice. In: Com-pendium of pharmaceuticals and specialties. Ottawa:Canadian Pharmicists Association; 2001.p. L63-65.
12. McNeece J. Interactions between grapefruit juiceand some drugs available in Australia [table].Aus-tralian Prescriber2002;25(2). Available: www.australianprescriber.com (accessed 2002 July 9).
280 JAMC 6 AOT 2002; 167 (3)
HE ALT H A ND DR UG AL E R TS
Table 1: Possible interactions between grapefruit juice (GJ)* and drugs metabolized by CYP3A4
Drug class Drug Possible adverse effectsIncreased oralbioavailability Management
Antiarrhythmics Amiodarone Arrhythmias Yes Avoid GJQuinidine None No None
Antibiotics Clarithromycin None No None
Antihistamines Terfenadine Arrhythmias, prolonged QT interval Yes Avoid GJ
Anxiolytics BuspironeDiazepamMidazolamTriazolam
Decreased psychomotor performance,increased sedation
YesYesYesYes
Avoid GJAvoid GJAvoid GJAvoid GJ
Calcium-channelblockers
AmlodipineFelodipineNifedipineNimodipineDiltiazemVerapamil
Tachycardia, hypotension
NoneNone
YesYesYesYesNoNo
Avoid GJAvoid GJAvoid GJAvoid GJ
NoneNone
Corticosteroids Ethinyl estradiol Unknown Yes Monitor for side effectsProgesterone Unknown Possible Monitor for side effectsPrednisone None No None
HMGCoA reductase
inhibitors
Atorvastatin
CerivastatinLovastatinPravastatinSimvastatin
Myopathy, headache, rhabdomyolysis
Yes
PossibleYesYesYes
Avoid GJ
Monitor for side effectsAvoid GJAvoid GJAvoid GJ
HIV protease inhibitors Saquinavir Unknown Yes Monitor for side effects
Immunosupressants CyclosporineTacrolimus
Renal/hepatic dysfunction, increasedimmunosuppression
YesYes
Avoid GJAvoid GJ
Neuropsychiatrics Carbamazepine Drowsiness, ataxia, nausea Yes Avoid GJClomipramine Drowsiness, respiratory depression Yes Monitor for side effectsPhenytoin None No None
Other Carvedilol Bradycardia, hypotension Possible Monitor for side effectsMethadone Respiratory depression, hypotension Possible Monitor for side effectsSildenafil Headache, f lushing, dyspepsia Possible Monitor for s ide effectsTheophylline None No NoneWarfarin None No None
*Grapefruit juice and the whole fruit.
Clinical significance unknown.