August 15, 2012

When Taking Drugs With Grapefruit Juice Can Be Beneficial

Chicago, IL—For years, pharmacists have been cautioning customers to avoid drinking grapefruit juice while taking prescription medications that treat conditions such as hypercholesterolemia, arrhythmias, and anxiety.

So it might be surprising to hear about a study that says grapefruit’s ability to increase absorption of medications actually can be beneficial in some cases.

In fact, researchers from the University of Chicago found that by drinking a glass of grapefruit juice a day, patients can derive three times the benefit from an anticancer drug as they would get just taking the drug by itself. That can both decrease side effects and manage high drug costs.

In a study published in August in Clinical Cancer Research, 8 ounces of grapefruit juice a day was shown to slow the body's metabolism of sirolimus, increasing patients’ drug levels by 350%. Ketoconazole, used as a comparison, increased sirolimus levels by 500%.

Sirolimus was the first of the mTOR inhibitors, developed to prevent rejection of transplanted organs but also having anticancer effects.

“Grapefruit juice, and drugs with a similar mechanism, can significantly increase blood levels of many drugs,” said study director Ezra Cohen, MD, a cancer specialist at the University of Chicago Medicine, “but this has long been considered an overdose hazard. Instead, we wanted to see if grapefruit juice can be used in a controlled fashion to increase the availability and efficacy of sirolimus.”

Within a few hours of ingestion, grapefruit inhibits enzymes in the intestine that break down drugs. The effect wears off gradually over a few days.

For the research, Cohen and colleagues organized three simultaneous phase 1 trials of sirolimus with 138 patients with incurable cancer and no known effective therapy. Patients received sirolimus alone, sirolimus plus ketoconazole, or sirolimus plus grapefruit juice.

The dose of sirolimus was increased over time so that patients got the greatest anticancer effect with the fewest side effects. The optimal dose for those taking sirolimus alone was about 90 mg per week, but doses above 45 mg were found to be intolerable because of gastrointestinal problems.

Optimal doses for the other two groups were much lower. Patients taking sirolimus plus ketoconazole needed only 16 mg per week to maintain the same systemic levels of the drug, while those taking sirolimus plus grapefruit juice needed between 25 and 35 mg of sirolimus per week.

“This is the first cancer study to harness this drug-food interaction,” the authors note.

No patients in the study had a complete response, the authors report, but about 30% of patients in the three trials had stable disease at some point. One patient receiving grapefruit juice had significant tumor shrinkage that lasted for more than 3 years.

Ketoconazole produced a slightly stronger drug-retention effect, but grapefruit juice is nontoxic and there is no risk of overdose, the authors point out, saying, “Therefore, we have at our disposal an agent that can markedly increase bioavailability…and, critically in the current environment, decrease prescription drug spending on many agents metabolized by P450 enzymes.”

One downside, which authors suggest can be mitigated by tests of enzyme levels, is the difference in how individuals react to grapefruit juice. In addition, grapefruit juice itself can vary in active ingredients.

“The variation in potency of the grapefruit juice itself may be far greater than the variation in the enzymes that break down sirolimus,” Cohen said.

Early in the research, investigators had used canned grapefruit juice donated by a Chicago-based grocery chain but had to switch to a frozen concentrate product supplied by the Florida Department of Citrus because it had more active ingredients.

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