Consuming 8 ounces of grapefruit juice increases sirolimus levels by 350%, allowing persons with cancer to take less toxic doses of the drug.        

This information was obtained from three simultaneous phase 1 studies involving 138 persons with advanced cancer. The trials employed an adaptive escalation design to find the doses of oral, weekly sirolimus alone or in combination with either the antifungal agent ketoconazole or grapefruit juice that would achieve similar blood concentrations as temsirolimus, the intravenously administered and approved prodrug of sirolimus.

An mTOR inhibitor, sirolimus is approved to help prevent organ rejection in transplant recipients, but may have anticancer effects as well. Grapefruit juice inhibits intestinal P450 enzymes that break down sirolimus as well as several other drugs.

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According to a statement from the University of Chicago Medical Center in Chicago, Illinois, where study director and cancer specialist Ezra Cohen, MD, practices, the effect of grapefruit juice begins within a few hours of ingestion and wears off gradually after a few days. Although this effect has long been considered an overdose hazard, “We wanted to see if grapefruit juice can be used in a controlled fashion to increase the availability and efficacy of sirolimus,” explained Cohen in the statement.

As Cohen and colleagues reported in Clinical Cancer Research, the optimal cancer-fighting dose for those taking sirolimus alone was found to be about 90 mg per week. But because nausea, diarrhea, and other serious gastrointestinal problems developed at doses above 45 mg, patients were switched to 45-mg doses administered twice a week.

Optimal sirolimus doses for the other two groups, however, were much lower: Persons who took ketoconazole plus sirolimus needed only 16 mg per week of the latter to maintain the same blood levels of the drug. By comparison, the grapefruit juice drinkers needed between 25 and 35 mg of sirolimus per week. Sirolimus blood levels increased by 500% with ketoconazole and by 350% with ingestion of 8 ounces of grapefruit juice daily. Despite the slightly stronger drug-retention effect of ketoconazole, grapefruit juice has the advantage of being nontoxic.

“We have at our disposal an agent [grapefruit juice] that can markedly increase bioavailability and, critically in the current environment, decrease prescription drug spending on many agents metabolized by P450 enzymes,” wrote the investigators.