.gif)
A glass a day of grapefruit juice lets patients derive the same benefits
from an anti-cancer drug as they would get from more than three times as much
of the drug by itself, according to a new clinical trial. The combination could
help patients avoid side effects associated with high doses of the drug and
reduce the cost of the medication.
Researchers at the University of
Chicago Medicine study the effects that foods can have on the uptake and
elimination of drugs used for cancer treatment. In a study published in August
in Clinical Cancer Research, they show that eight ounces a day of grapefruit
juice can slow the body's metabolism of a drug called sirolimus, which has been
approved for transplant patients but may also help many people with cancer.
Patients who drank eight ounces a
day of grapefruit juice increased their sirolimus levels by 350 percent. A drug
called ketoconazole that also slows drug metabolism increased sirolimus levels
by 500 percent.
"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."
Grapefruit juice's pharmaceutical
prowess stems from its ability to inhibit enzymes in the intestine that break
down sirolimus and several other drugs. The effect begins within a few hours of
what the researchers refer to as "grapefruit juice administration." It
wears off gradually over a few days.
Cohen and colleagues organized
three simultaneous phase-1 trials of sirolimus. Patients received only
sirolimus, sirolimus plus ketoconazole, or sirolimus plus grapefruit juice.
They enrolled 138 patients with incurable cancer and no known effective
therapy.
The first patients started with
very low sirolimus doses, but the amounts increased as the study went on, to
see how much of the drug was required in each setting to reach targeted levels,
so that patients got the greatest anti-cancer effect with the least side
effects.
The optimal cancer-fighting dose
for those taking sirolimus was about 90 mg per week. At doses above 45 mg,
however, the drug caused serious gastrointestinal problems, such as nausea and
diarrhea, so patients taking sirolimus alone switched to 45 mg twice a week.
The 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 levels of drug in the blood. 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, but about 30 percent of patients in the three trials had stable
disease, meaning a period when their cancers did not advance. One patient
receiving grapefruit juice had a partial response—significant tumor
shrinkage—that lasted for more than three years.
Although ketoconazole produced a
slightly stronger drug-retention effect, grapefruit juice has the advantage
that it is non-toxic, with no risk of overdose. "Therefore," the
authors wrote, "we have at our disposal an agent that can markedly
increase bioavailability (in this study by approximately 350%) and, critically
in the current environment, decrease prescription drug spending on many agents
metabolized by P450 enzymes."
Sirolimus was the first of a
series of drugs, known as mTOR inhibitors, that were developed to prevent
rejection of transplanted organs but that also have anti-cancer effects. As the
first of its class, it was also the first to come off patent, making it less
costly. "Further cost savings," the authors suggest, could be
realized "by combining the drug with agents that inhibit its
metabolism."
Because different people produce
varied amounts of the enzymes that break down sirolimus, the effect of
grapefruit juice can vary, but tests of enzyme levels may be able to predict
how an individual patient will respond.
"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. An early version of the
study used canned grapefruit juice, generously donated by a Chicago-based
grocery chain. But tests of the product found it lacked the active ingredients.
So the researchers shifted to a frozen concentrate product supplied by the
Florida Department of Citrus.
Provided
by University
of Chicago Medical Center
No comments:
Post a Comment