Grapefruit Effect On Drug Levels Has Sweeter Side

By SYLVIA PAGÁN WESTPHAL
WSJ November 27, 2007

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 Dr. 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 Dr. Harris. "This is not to be used to help get the ninth non-sedating antihistamine to the market."
Don't Try This at Home
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% 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 Dr. 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.
The quest to capture the grapefruit effect underscores another important aspect of how drugs are metabolized: The food we ingest can have a profound impact on drug performance. It's why pharmaceutical companies routinely test their drug candidates under fasting and nonfasting conditions. Even changing the fat content of a meal can have a major effect on a drug's efficacy.
A case in point is Tykerb, an anticancer drug manufactured by GlaxoSmithKline PLC. A recent company-sponsored study showed that the drug's blood levels increased by 167% when taken with a low-fat meal, compared with taking the drug on an empty stomach -- and by 325% after a high-fat meal.
Drs. Ratain and Cohen argue that these kinds of food-drug interactions should be explored to lower drug costs. In a recent editorial in the Journal of Clinical Oncology, the researchers ruffled some industry feathers by arguing that taking Tykerb with food (the label says not to) might allow patients to take lower doses, leading to a potential cost savings of 60% off the drug's $2,900-a-month price tag. Savings could be about 80% if Tykerb were taken with grapefruit juice as well, they said, since the drug interacts with CYP3A4.
Other anticancer drugs are broken down by CYP3A4, posing the "compelling" possibility of using grapefruit juice to lower their cost as well, says Dr. Cohen. "Oral oncology therapies are costing $3,000 to $5,000 a month. So it's almost like a new world when it comes to drugs costs. If we can lower the costs of those by 50%, you're talking about hundreds of millions of dollars saved," Dr. Cohen says.
But not everyone agrees it would be wise to "prescribe" food or drinks to patients as a drug booster. For one, the approach doesn't address the issue of patient variability. In the case of Tykerb, giving the drug with a high-fat meal increased blood levels differently depending on the person, says Peter Ho, head of cancer-drug discovery at Glaxo. That's why the company decided, together with the Food and Drug Administration, that the label should recommend taking it on an empty stomach. "At the low end it increased by twofold, but at the high end some subjects had as much as a 24-fold increase, and that's a problem," Dr. Ho says.
There is "no question" that grapefruit juice will increase the blood levels of rapamycin, adds Wyeth's head of medical affairs Joseph Camardo, but he is less convinced that the effect can be consistent. "Our position is, it is not likely to bring the variability to an acceptable level," he says.
Another concern is the variation in quality among juice brands. "The actual amount of these active ingredients varies substantially between grapefruit juices and even the same lot," says researcher Paul Watkins from the University of North Carolina in Chapel Hill, who has done research on the grapefruit compounds.
Dr. Harris believes that one way to address some of these concerns is to standardize the grapefruit compounds into a pill with a defined dose. That would take away at least one of the variables.
"If you take the components out and put them in a pill then it becomes something that's a little more manageable," says Wyeth's Dr. Camardo.
Blocking Efficacy
Meanwhile, the grapefruit continues to surprise the scientific community. Recently, another class of compounds in the fruit was found to block a different set of proteins in the intestine known as "transporters." These transporter proteins actively shuttle drugs from the gut into the bloodstream. Blocking these transporters prevents some drugs from entering the system. This finding may mean that grapefruit is contraindicated with certain drugs for a whole new set of reasons.
One such compound called naringin affects the efficacy of the popular allergy drug Allegra by blocking these transporters. "Even a normal glass of juice will reduce the effects of Allegra by half," says Dr. Bailey, whose team made the discovery last year. "It's the tip of the iceberg," he adds. "Big pharma is very interested."
Write to Sylvia Pagán Westphal at sylvia.westphal@wsj.com