There's a sweet side to grapefruit's drug effect

Many patients know that grapefruit juice doesn't mix with certain popular drugs -- notably cholesterol-busting statins such as Zocor and Lipitor. Too much Citrus paradisi, and the blood levels of some medicines can rise to toxic levels.

But the grapefruit effect may have a silver lining. Research suggests the fruit's ability to interact with drugs may be exploited to make some medicines more powerful.

At the University of Chicago, scientists are studying grapefruit juice in combination with an experimental anticancer compound, hoping to boost the drug's weak effects. In Florida, Bioavailability Systems LLC, a small biotechnology company, claims to have purified the grapefruit compounds responsible for the boosting effect and has been able to improve the blood levels of an anti-HIV drug. "This is definitely a lemons to lemonade story," says James Harris, founder and chief scientific officer of the company.

The approach aims to tackle a major problem for drug manufacturers: the great degree of variation in how people absorb drugs. Partly to blame is the fact that individuals have different levels of an enzyme in the intestines and liver, called CYP3A4, that breaks down drugs before they even have the chance to get into the bloodstream. People with very active CYP3A4 get lower amounts of drugs into their systems than those with low levels of the enzyme.

But powerful compounds in the grapefruit called furanocoumarins obliterate CYP3A4 in the gut. The result: More drug gets into the bloodstream.

For some anticholesterol statins, for example, taking one tablet with a glass of grapefruit juice "is like taking at least 10 tablets with a glass of water," says David Bailey, a pharmacologist at the University of Western Ontario who discovered the grapefruit effect in the early 1990s. It's why some major blockbusters, like the statin Mevacor or the anticancer drug Gleevec, contain warnings against taking these drugs with grapefruit juice.

But for certain drugs that have a hard time reaching optimal blood levels at prescribed doses, some doctors are interested in intentionally boosting the effects with grapefruit.

Generally, the idea would be to give a booster to all patients who are taking a weak drug. While some patients may have naturally low levels of the CYP3A4 enzyme and thus wouldn't need it, there's no practical way to test individuals right now, so researchers are using a blanket approach. As long as a drug does not have what is known as a "narrow therapeutic window" -- meaning that a relatively small increase in dose makes it toxic -- boosting shouldn't necessarily lead to large increases in side effects, the theory goes.

"More patients will receive meaningful therapy from the one-dose-fits-all approach," says Harris.

Still, many drugs, such as the blood thinner Warfarin and certain antibiotics, do have a narrow window. For such drugs, a blanket approach to boosting would be too risky. Boosting should be reserved for only a few disease areas -- like infectious diseases or cancer -- where the risk of side effects from higher drug levels is worth taking, says Harris. "This is not to be used to help get the ninth non-sedating antihistamine to the market."

Experts also warn that people should not try boosting on their own to make an expensive medication last longer or make their medicines more effective. Only a clinical trial can show whether the approach is helpful for an individual drug, they say. And it is impossible to know who will respond too strongly or not at all to the grapefruit effect. In people who take multiple drugs, the approach could backfire by interfering with the effects of other medicines that are already working well without boosting.

In one effort to home in on the best way to exploit the grapefruit effect, researchers Ezra Cohen and Mark Ratain at the University of Chicago are conducting a 30-patient study of grapefruit juice with an experimental cancer drug called rapamyicin. The drug -- sold by Wyeth as an immunosuppressant -- is usually poorly absorbed into the blood. Normally only about 14 percent of the amount in a pill gets into people's bloodstream, but so far, the researchers have seen that when combined with grapefruit juice, the blood levels of the drug can increase up to fourfold, says Cohen. (The scientists get a "standardized" grapefruit juice concentrate from the Florida Department of Citrus, which analyzed different batches to find one with high levels of furanocoumarins.)

Bioavailability Systems studied its grapefruit extract with a modestly effective anti-HIV drug and saw an average 40-fold increase in blood levels, says Dr. Harris. The company has created synthetic mimics of the grapefruit compounds that it plans to test in human trials next year.