Affected drugs
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The following drugs are affected by CYP3A4 inhibition with grapefruit compounds:
Amphetamines
List of Amphetamines That Interact With The Cytochrome P450 CYP2D6 enzyme:
Research has been done on the interaction between amphetamines and The Cytochrome P450 CYP2D6 enzyme, and researchers concluded that some parts of substrate molecules contribute to the binding of the enzyme. [11]
Additional drugs found to be affected by grapefruit juice include, but are not limited to:
- Some statins such as atorvastatin (Lipitor), lovastatin (Mevacor) and simvastatin (Zocor, Simlup, Simcor, Simvacor); however, pravastatin (Pravachol), fluvastatin (Lescol) and rosuvastatin (Crestor) are unaffected by grapefruit.[12][13]
- dihydropyridines including felodipine (Plendil), nicardipine (Cardene), nifedipine, nisoldipine (Sular) and nitrendipine (Bayotensin)[12]
- losartan (Cozaar)[12]
- repaglinide (Prandin)[12]
- verapamil (Calan SR, Covera HS, Isoptin SR, Verelan)[12]
- buspirone (Buspar): Grapefruit juice increased peak and AUC plasma concentrations of buspirone 4.3- and 9.2-fold, respectively, in a randomized, 2-phase, ten-subject crossover study.[14]
- levothyroxine (Eltroxin, Levoxyl, Synthroid): the absorption of levothyroxine is affected by grapefruit juice.[clarification needed] [15]
- Antiarrhythmics including amiodarone (Cordarone), dronedarone (Multaq), quinidine (Quinidex, Cardioquin, Quinora), disopyramide (Norpace), propafenone (Rythmol) and carvedilol (Coreg)[12]
- Erectile dysfunction drugs sildenafil (Viagra), tadalafil (Cialis) and vardenafil (Levitra)[12][16]
- The anti-migraine drugs ergotamine (Cafergot, Ergomar), amitriptyline (Elavil, Endep, Vanatrip) and nimodipine (Nimotop)[12]
- fluvoxamine (Luvox, Faverin, Fevarin and Dumyrox)[17]
- codeine:[18]
- cyclosporine (Neoral): Blood levels of cyclosporine are increased if taken with grapefruit juice. A plausible mechanism involves the combined inhibition of enteric CYP3A4 and P-glycoprotein, which potentially leads to serious adverse events (e.g., nephrotoxicity). Blood levels of tacrolimus (Prograf) can also be equally affected for the same reason as cyclosporine, as both drugs are calcineurin inhibitors.[19]
- exemestane, aromasin, and by extension all estrogen-like compounds and aromatase inhibitors which mimic estrogen in function will be increased in effect, causing increased estrogen retention and increased drug retention.[20][unreliable medical source?]
- omeprazole (Losec, Prilosec)[21]
- zolpidem (Ambien): Little or no interaction with grapefruit juice.[22]
- oxycodone: metabolized by the cytochrome P450 system, specifically CYP3A4, of which the bergamottin flavonoid is a strong inhibitor[23]
- quetiapine (Seroquel)[24]
- methadone: Inhibits the metabolism of methadone and raises serum levels.[25]
- buprenorphine: Metabolized into norbuprenorphine by cytochrome-P450 isoenzyme 3A4[26]
- trazodone (Desyrel): Little or no interaction with grapefruit juice.[22]
- anthelmintics: Used for treating certain parasitic infections; includes praziquantel
- imatinib (Gleevec): Although no formal studies with imatinib and grapefruit juice have been conducted, the fact that grapefruit juice is a known inhibitor of the CYP 3A4 suggests that co-administration may lead to increased imatinib plasma concentrations. Likewise, although no formal studies were conducted, co-administration of imatinib with another specific type of citrus juice called Seville orange juice (SOJ) may lead to increased imatinib plasma concentrations via inhibition of the CYP3A isoenzymes. Seville orange juice is not usually consumed as a juice because of its sour taste, but it is found in marmalade and other jams. Seville orange juice has been reported to be a possible inhibitor of CYP3A enzymes without affecting P-glycoprotein when taken concomitantly with cyclosporine.[27]
- erlotinib (Tarceva) [28]
- In a mouse study, blood concentrations of acetaminophen/paracetamol (Tylenol) were found to be increased by white and pink grapefruit juice, with the white juice acting faster.[29]
- fexofenadine (Allegra) [30]
- warfarin[31]
- lamotrigine
Mechanism of the interaction
The CYP3A4 isoform of cytochrome P450 is located in both the liver and the enterocytes. Many oral drugs undergo first-pass (presystemic) metabolism by the enzyme. Several organic compounds found in grapefruit and specifically in grapefruit juice exert inhibitory action on drug metabolism by the enzyme. It has been established that a group of compounds called furanocoumarins are responsible for this interaction, and not flavonoids as was previously reported.[32] The list of active furanocoumarins found in grapefruit juice includes: bergamottin, bergapten, bergaptol and 6′,7′-dihydroxybergamottin.
This interaction is particularly dangerous when the drug in question has a low therapeutic index, so that a small increase in blood concentration can be the difference between therapeutic effect and toxicity. Grapefruit juice inhibits the enzyme only within the intestines, not in the liver or elsewhere in the body, and does not impact injected drugs. The degree of the effect varies widely between individuals and between samples of juice, and therefore cannot be accounted for a priori.
Another mechanism of interaction is possibly through the P-glycoprotein (Pgp) that is localized in the apical brush border of the enterocytes. Pgp transports lipophilic molecules out of the enterocyte back into the intestinal lumen. Drugs that possess lipophilic properties are either metabolised by CYP3A4 or removed into the intestine by the Pgp transporter. Both the Pgp and CYP3A4 may act synergistically as a barrier to many orally administered drugs. Therefore, their inhibition (both or alone) can markedly increase the bioavailability of a drug.
The interaction caused by grapefruit compounds lasts for up to 72 hours, and its effect is the greatest when the juice is ingested with the drug or up to 4 hours before the drug. [33][34][35]
References
- Bailey, David G.; Dresser, George; Arnold, J. Malcolm O. (2012). “Grapefruit-medication interactions: Forbidden fruit or avoidable consequences?”. Canadian Medical Association Journal (Canadian Medical Association). doi:10.1503/cmaj.120951. edit
- “– Hybrid grapefruit safe for prescription meds”. Futurity.org. Retrieved 2013-01-28.
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- Sugimoto K, Araki N, Ohmori M, et al. (2006). “Interaction between grapefruit juice and hypnotic drugs: comparison of triazolam and quazepam”. Eur. J. Clin. Pharmacol. 62 (3): 209–15. doi:10.1007/s00228-005-0071-1. PMID 16416305.
- “Ritonavir (Norvir)”. HIV InSite. UCSF. 2006-10-18. Retrieved 2008-03-12.
- Lee AJ, Chan WK, Harralson AF, Buffum J, Bui BC. (1999). “The effects of grapefruit juice on sertraline metabolism: an in vitro and in vivo study.”. Clin Ther. 21 (11): 1890–9. doi:10.1016/S0149-2918(00)86737-5. PMID 10890261.
- “Interactions of amphetamine analogs with human liver CYP2D6”. National Center for Biotechnology Information, U.S. National Library of Medicine.
- “SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions.”. Structural Bioinformatics Group, Institute of Physiology, Charité-University Medicine Berlin.
- “Methamphetamine-mediated oxidative stress induces astrocyte apoptosis via cytochrome P450 2E1”. National Center for Biotechnology Information, U.S. National Library of Medicine.
- “potent inhibition of P450 gene CYP2D6 on d-amphetamine, methylphenidate, and cocaine”. Department of Pharmacology, University of Toronto, Ontario, Canada.
- “Metabolism/ Metabolites of amphetamines interacting with The Cytochrome P450 CYP2D6 enzyme”. U.S. National Library of Medicine.
- Bailey DG, Dresser GK (2004). “Interactions between grapefruit juice and cardiovascular drugs”. Am J Cardiovasc Drugs 4 (5): 281–97. doi:10.2165/00129784-200404050-00002. PMID 15449971.
- Lilja JJ, Kivistö KT, Neuvonen PJ (August 1999). “Grapefruit juice increases serum concentrations of atorvastatin and has no effect on pravastatin”. Clin. Pharmacol. Ther. 66 (2): 118–27. doi:10.1053/cp.1999.v66.100453001. PMID 10460065.
- Lilja JJ, Kivistö KT, Backman JT, Lamberg TS, Neuvonen PJ (1998). “Grapefruit juice substantially increases plasma concentrations of buspirone*”. Clinical Pharmacology & Therapeutics 64 (6): 655–660. doi:10.1016/S0009-9236(98)90056-X. PMID 9871430. edit
- Lilja, JJ; Laitinen, K; Neuvonen, PJ (September 2005). “Effects of grapefruit juice on the absorption of levothyroxine.”. British Journal of Clinical Pharmacology 60 (3): 337–41. doi:10.1111/j.1365-2125.2005.02433.x. PMC 1884777. PMID 16120075.
- Jetter A, Kinzig-Schippers M, Walchner-Bonjean M, et al. (2002). “Effects of grapefruit juice on the pharmacokinetics of sildenafil”. Clin. Pharmacol. Ther. 71 (1): 21–9. doi:10.1067/mcp.2002.121236. PMID 11823754.
- H. Hori, R. Yoshimura, N. Ueda, S. Eto, K. Shinkai, S. Sakata, O. Ohmori, T. Terao and J. Nakamura (2004). “Fluvoxamine, In Vivo Study” (PDF). J Clin Psychopharmacol 23 (4): 422–424. doi:10.1097/01.jcp.0000085423.74359.f2. PMID 12920426.
- Gasche Y, Daali Y, Fathi M, et al. (December 2004). “Codeine intoxication associated with ultrarapid CYP2D6 metabolism”. N. Engl. J. Med. 351 (27): 2827–31. doi:10.1056/NEJMoa041888. PMID 15625333. Retrieved 2008-05-11.
- “Further characterization of a furanocoumarin-free grapefruit juice on drug disposition: studies with cyclosporine“, American Journal of Clinical Nutrition, Vol. 87, No. 4, 863-871, April 2008.
- “[1] “Somelabel”
- http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2014525/ Mouly and Paine, Br J Clin Pharmacol. 2001 August; 52(2): 216–217.
- “Grapefruit and medication: A cautionary note”. Health.harvard.edu. Retrieved 2013-01-28.
- Wikipedia article on oxycodone metabolism; pharmaceutical insert w/ Purdue OxyContin tablets – http://en.wikipedia.org/wiki/Oxycodone#Metabolism
- “Grapefruit Interactions”. healthCentral. Retrieved 2013-01-28.
- Messaoud Benmebarek MD, Et al., M; Devaud, C; Gex-Fabry, M; Powell Golay, K; Brogli, C; Baumann, P; Gravier, B; Eap, CB (17 March 2004). “Effects of grapefruit juice on the pharmacokinetics of the enantiomers of methadone”. Clinical Pharmacology & Therapeutics 76 (1): 55–63. doi:10.1016/j.clpt.2004.03.007. PMID 15229464. Retrieved 2009-03-13.
- Elkader, A; Sproule, B (July 2005). “Bluprenorphine – Clinical pharmacokinetics in the treatment of opioid dependence”. Clinical Pharamacokinetics 44 (7): 661–680. doi:10.2165/00003088-200544070-00001. PMID 15966752. Retrieved 2013-02-24.
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- Dasgupta, Amitava; Meredith A. Reyes; Semyon A. Risin; Jeffrey K. Actor (3 December 2008). “Interaction of white and pink grapefruit juice with acetaminophen (paracetamol) in vivo in mice”. Journal of Medicinal Food 11 (4): 795–8. doi:10.1089/jmf.2008.0059. ISSN 1557-7600. PMID 19053875.
- Dresser, GK; Kim RB; Bailey DG (March 2005). “Effect of grapefruit juice volume on the reduction of fexofenadine bioavailability: possible role of organic anion transporting polypeptides.”. Clinical Pharmacological Therapeutics 77 (3): 170–7. PMID 15735611.
- Jellin J.M., et al. Pharmacist’s Letter/Prescriber’s Letter of Natural Medicines Comprehensive Database. 7th ed. Stockton, CA: Therapeutic Research Faculty. 2005. 626-629
- Paine MF, Widmer WW, Hart HL, et al. (May 2006). “A furanocoumarin-free grapefruit juice establishes furanocoumarins as the mediators of the grapefruit juice-felodipine interaction”. The American journal of clinical nutrition 83 (5): 1097–105. PMID 16685052.
- 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.
- http://pharmacistanswers.com/grapefruit-juice-drug-interactions.html
- Greenblatt DJ, von Moltke LL, Harmatz JS, et al. Time course of recovery of cytochrome P450 3A function after single doses of grapefruit juice. Clin Pharmacol Ther 2003;75:121-9.
- Bakalar, Nicholas (2006-03-21). “Experts Reveal the Secret Powers of Grapefruit Juice”. The New York Times. p. F6. Retrieved 2008-05-21.
- Gross AS, Goh YD, Addison RS, Shenfield GM (April 1999). “Influence of grapefruit juice on cisapride pharmacokinetics”. Clin. Pharmacol. Ther. 65 (4): 395–401. doi:10.1016/S0009-9236(99)70133-5. PMID 10223776.
External links
- USDA Database of Flavonoid content of food
- Graedon’s Guide to Grapefruit Interactions. PDF (34.6 KB)
- Appendix 1: Grapefruit Interacting Drugs and Associated Oral Bioavailability, Adverse Event(s), Risk Ranking and Potential Alternative Medications Appendix to: Bailey DG, Dresser G, Arnold JMA. Grapefruit and medication interactions: forbidden fruit or avoidable consequences? CMAJ 2012; doi:10.1503/cmaj.120951. Copyright © 2012 Canadian Medical Association or its licensors
- Interactions of amphetamine analogs with human liver CYP2D6.
- The Metabolomics Innovation Centre (TMIC)
- a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions.
- Drug interactions with grapefruit juice. Extent, probable mechanism and clinical relevance.
- methamphetamine-mediated oxidative stress induces astrocyte apoptosis via cytochrome P450 2E1
- Flavonoids and polymer derivatives as CYP3A4 inhibitors for improved oral drug bioavailability.
- Grape fruit juice-drug interactions.
- SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions.
- potent inhibition of P450 gene CYP2D6 on d-amphetamine, methylphenidate, and cocaine
- a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions
- Functional pharmacogenetics of cytochromes P450 involved in drug biotransformation
- Cytochrome P450 interactions with the CYP2D6
- Dexamfetamine Cytochrome P450 interaction, Structure, and Cyp IAs Vault
- Methylphenidate Cytochrome P450 interaction, Structure, and Cyp IAs Vault
- Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007)
- 3D structure of CYP2D6 (enzyme that interacts with amphetamines)
- Cytochrome P450 CYP2D6 enzyme is responsible for the metabolism of at least 20% of known drugs.
- Schematic diagram of Cytochrome P450 CYP2D6 enzyme
- Ribbon diagram of the CYP2D6 enzyme structure
- diagram of CYP2D6’s ribbon “right foot”-shaped active site cavity
