List of drugs affected by grapefruit

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Grapefruit and grapefruit juice have the potential to interact with numerous drugs. A number of organic compounds, identified as furanocoumarin derivates, interfere with the hepatic and intestinal enzyme cytochrome P450 isoform CYP3A4 and are therefore primarily responsible for the interaction. However, bioactive compounds in grapefruit juice may also interfere with P-glycoprotein and organic anion transporting polypeptides (OATPs) either increasing or decreasing bioavailability of a number of drugs.

History

In 1989 a pharmacological study evaluated the possibility of an interaction between ethanol ingestion and medication with the dihydropyridine calcium channel blocker - felodipine. Grapefruit juice was used as a flavouring additive during the test. The results of study showed several-fold increase of felodipine concentrations compared to results obtained in other investigations of the drug. Additionally, there were lower blood pressure readings and more adverse effects compared to the group of subjects on felodipine alone. Further investigations revealed that grapefruit juice strikingly elevated felodipine bioavailability and could influence its other pharmacokinetic and pharmacodynamic properties.[1]

Affected drugs

The following drugs are affected by CYP3A4 inhibition with grapefruit compounds:

Additional drugs found to be affected by grapefruit juice include, but are not limited to:

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.[14] 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 success and toxicity. Grapefruit juice only inhibits the enzyme 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, therefore it 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 24 hours and its effect is the greatest when the juice is ingested with the drug or up to 4 hours before the drug. [15]

The flavonoid existing in highest concentration in grapefruit juice is naringin, which in humans is metabolised to naringenin. Other flavonoids exist in grapefruit juice in lower concentrations as well. Orange juice does not contain naringin in as high a concentration, instead containing hesperetin. It is sometimes recommended as a substitute. Juice of limes and Seville oranges can also inhibit drug metabolism, however, as can apple juice with some drugs.

Drugs affected by grapefruit juice[16]
Drug class Major Interactions Minor interactions
Calcium channel antagonists Plendil
Cardene (Nicardipine)
Procardia (Nifedipine)
Nimotop
Sular
DynaCirc
Antiarrhythmics Cordarone
Multaq
Statins (HMG-CoA reductase inhibitors) Mevacor (Lovastatin) Lipitor
Baycol (off the market)
Immunosuppressants Sandimmune (Cyclosporine)
Prograf
Rapamune
Mercaptopurine
Dissociatives Dextromethorphan
Sedatives, hypnotics, and anxiolytics Buspar Halcion
Versed
Valium (Diazepam)
Sonata (Zaleplon)
Alprazolam
Other psychotropics Tegretol (Carbamazepine)
Desyrel
Serzone
Seroquel
Fluvoxamine
Antihistamines Seldane (off the market)
Hismanal (off the market)
Claritin (Loratadine)
HIV protease inhibitors Invirase
Norvir
Viracept
Agenerase
Hormones Ortho-Cept (Ethinyl estradiol)
Depo-Medrol (Methylprednisolone)
Other drugs Viagra
Propulsid[17]

References

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  7. 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. 
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  11. Wikipedia article on Oxycodone metabolism; pharmaceutical insert w/ Purdue OxyContin tablets - http://en.wikipedia.org/wiki/Oxycodone#Metabolism
  12. Messaoud Benmebarek MD, M; Devaud, C; Gex-Fabry, M; Powell Golay, K; Brogli, C; Baumann, P; Gravier, B; Eap, CB; et al. (17 March 2004). "ffects of grapefruit juice on the pharmacokinetics of the enantiomers of methadone". Clinical Pharmacology & Therapeutics (2004). Swiss Federal Office of Public Health. 76 (1): 55. doi:10.1016/j.clpt.2004.03.007. PMID 15229464. Retrieved 2009-03-13. 
  13. http://en.wikipedia.org/wiki/Buprenorphine#Pharmacology_and_pharmacokinetics
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  16. Bakalar, Nicholas (2006-03-21). "Experts Reveal the Secret Powers of Grapefruit Juice". The New York Times. p. F6. Retrieved 2008-05-21. 
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