A New Twist on Grapefruit: Boosting Cancer Drug Benefits With Less Toxicity

As nurses, you know that your patients should not drink grapefruit juice while on chemotherapy, since it can interfere with absorption of a variety of medications, increasing drug blood levels and heightening the risk of overdose.

But researchers from the University of Chicago and the University of Texas Medical School at Houston have put an interesting twist on the grapefruit juice effect: In what they described in a news release as "the first cancer study to harness this drug-food interaction," they used grapefruit juice as part of a chemotherapy regimen to dramatically lower the therapeutic dose needed -- and reduce the toxic side effects of treatment.

Reporting online in Clinical Cancer Research, associate professor of medicine Ezra E. Cohen, MD, and colleagues found that drinking eight ounces of grapefruit juice daily significantly slowed metabolism of the immunosuppressant sirolimus (Rapamune) in patients with advanced cancer. In fact, the patients had the same benefits from sirolimus that they would have gotten from three times as much of the drug if it were given alone.

Sirolimus is an orally administered mTOR (mammalian target of rapamycin) inhibitor that is FDA-approved for preventing organ rejection in kidney transplant patients, and it is under clinical investigation for management of patients with cancer (for example, as prophylaxis against graft -- versus host disease in patients undergoing stem cell transplants). Its prodrug, temsirolimus (Temodar), is administered intravenously and is FDA-approved to treat certain types of brain cancer.

Grapefruit juice inhibits cytochrome P450 enzymes in the intestine that normally breaks down certain drugs. This effect occurs several hours after ingestion and disappears after a few days.

In their dose-finding study of 138 patients with advanced incurable cancer from three phase I trials, Dr. Cohen and colleagues assessed the therapeutic effects of oral, weekly sirolimus alone or in combination with either ketoconazole (an antifungal that also slows drug metabolism) or grapefruit juice. The investigators wanted to see if grapefruit juice or ketoconazole could boost blood levels of sirolimus to therapeutic levels typically achieved with the prodrug, temsirolimus.

The target sirolimus AUC (area under the concentration curve, in this case, 3,810 ng-h/mL), or optimal therapeutic blood concentration, was achieved at sirolimus doses of 90 mg with sirolimus alone, 16 mg with sirolimus plus ketoconazole, and 25 mg with sirolimus plus grapefruit juice. In effect, ketoconazole increased the sirolimus bioavailability (AUC) by about 500 percent, and grapefruit juice increased sirolimus bioavailability by 350 percent. However, gastrointestinal effects (nausea, diarrhea) were seen at sirolimus doses of 45 mg and higher, underscoring the benefit of enhancing its bioavailability at lower doses.

Because grapefruit juice is nontoxic, with no risk of overdose, Dr. Cohen and colleagues wrote about grapefruit juice: "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."

No patients in the study had a complete response, but about one third had stable disease, and one patient who received grapefruit juice had a partial response (tumor shrinkage) lasting more than three years.

The news release from the University of Chicago says the grapefruit juice effect is variable because of individual variation in levels of the enzymes that break down sirolimus, but that tests of these enzyme levels may help to predict how a patient will respond. Not all grapefruit juice is equal either. The researchers found juice made from fresh, frozen concentrate was most effective.