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Grapefruit May Make
Medicines More Powerful

Last time we turned our attention to grapefruit, it was to blast a study that purported to link grapefruit to breast cancer. We entitled that piece Beware Of Headlines About Dubious Grapefruit Cancer Study.

We felt horrible for the grapefruit industry as we expressed at that time:

Those poor grapefruit farmers. First they get hit because their high-usage market of elderly people is scared off because of drug interactions and now this.

Now, however, showing that the world works in mysterious ways, there are new indications that the very same dynamic scaring off many elderly people from grapefruit consumption may lead medicine to harness the power of grapefruit to increase the effectiveness of new and often expensive medicines. The Wall Street Journal called the story, Grapefruit Effect On Drug Levels Has Sweeter Side:

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.

It is a long way from this insight to clinical trials and some actual useful therapy. But there is science being done:

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.)

The article focuses on grapefruit but, by implication, the issues it studies raises considerations for the broader industry:

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.

Now the question is: Can this knowledge be used in a productive way?

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.

On the one hand, we can imagine a world where doctors routinely prescribe grapefruit or grapefruit juice along with certain drugs, but, very possibly, scientists will look to standardize formulations in a pill:

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.

And the piece pointed out there are some new concerns over other compounds in grapefruit that may cause it to be counter-indicated:

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.”

We don’t get hysterical when we see negative studies, and we restrain our enthusiasm when we get positive studies. Tis many a slip ‘tween the cup and the lip or, put another way, years of research are usually required to figure these things out and they rarely work out as first expected.

Yet the idea that food and drink will effect the efficacy of medicines seems uncontroversial. Looking for opportunities here may yet give Fruits & Veggies — More Matters a particularly useful target.

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