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Drug Delivery Made Better with Grapefruit Juice?

A pink grapefruit (Citrus paradisi).

Pharmacists often decorate your prescription medications in colorful arrays of "auxiliary label" stickers.  The labels may advise you to take the medication with or without food, with plenty of water, or to avoid dairy products, alcohol, antacids - even grapefruit juice.

Why is it important to avoid grapefruit juice with certain medications?  The first clue came 20 years ago from a study designed to determine the effects of alcohol consumption on the metabolism of felodipine (CAS Registry Number 72509-76-3), an anti-hypertensive drug.¹  Before taking a dose of felodipine, study participants were instructed to drink a glass of ethanol-spiked grapefruit juice, a cocktail that effectively masked the taste of alcohol.  The surprising findings from the study were first published in 1989 in Clinical and Investigative Medicine:

• "Felodipine bioavailability was not influenced by ethanol.  However felodipine plasma concentrations greatly exceeded the expected concentrations, possibly due to a pharmacokinetic interaction with the grapefruit juice vehicle."²

Substances in grapefruit (Citrus paradisi) thought to cause elevated blood levels of felodipine include bergamottin (CAS Registry Number 7380-40-7) and 6',7'-dihydroxybergamottin (CAS Registry Number 145414-76-2).³  These and other phenolic furanocoumarins have been shown to block the activity of cytochrome P450 3A4, an enzyme responsible for the metabolism of felodipine and many other drugs.  While the "grapefruit juice effect" in drug metabolism is often perceived as a safety concern, a recent study of the anti-cancer drug rapamycin (CAS Registry Number 53123-88-9) highlights a novel strategy to exploit the effect for improved drug delivery.⁴  According to a press release issued by the University of Chicago Medical Center:

• "This study showed that substances known as furanocoumarins, plentiful in some forms of grapefruit juice, can decrease the breakdown of rapamycin.  This makes the drug reach higher levels in the bloodstream, two to four times the levels seen without a juice boost, and thus increases the amount of the drug that reaches its target."⁴

You can use SciFinder or STN to search the CAS databases for additional information about grapefruit furanocoumarins, felodipine, rapamycin, and cytochrome P450 enzymes.  If your organization is enabled to use the web version of SciFinder, you can click the links in this article to directly access details of the substances and references.

Contributed by
Peter S. Carlton, Ph.D.
CAS Communications

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References

1. Bailey, D.G.; Malcolm, J.; Arnold, O.; Spence, J.D. Grapefruit juice-drug interactions. Br. J. Clin. Pharmacol. 1998, 46, 101-110.
2. Bailey, D.G.; Spence, J.D.; Edgar, B.; Bayliff, C.D.; Arnold, J.M.O. Ethanol enhances the hemodynamic effects of felodipine. Clin. Invest. Med. 1989, 12, 357-362.
3. Paine, M.F.; Widmer, W.W.; Hart, H.L.; Pusek, S.N.; Beavers, K.L.; Criss, A.B.; Brown, S.S.; Thomas, B.F.; Watkins, P.B. A furanocoumarin-free grapefruit juice establishes furanocoumarins as the mediators of the grapefruit juice-felodipine interaction. Am. J. Clin. Nutr. 2006, 83, 1097-1105.
4. University of Chicago Medical Center. http://www.uchospitals.edu/ (accessed April 28, 2009).

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