By Abigail Zuger
For four years, the patient was one of Dr. Paul Pizarik's bigger problems: a 63-year-old Arizona man with heart, lung and kidney disease, and blood pressure that stayed dangerously high despite combinations of a half-dozen different advanced medications.
And then suddenly, to Pizarik's great surprise, the man's pressure dropped into perfect control. It had been magically reduced by nothing more complicated than a six-ounce glass of grapefruit juice that the patient had decided to add to his morning pills.
A few weeks later, his pressure plunged so low that his medication had to be changed all over again.
Researchers have known since 1989 that when some of the common blood-pressure pills called calcium-channel blockers were washed down with grapefruit juice, far more of the drugs reached the blood than when they were taken with a swallow of water instead.
But it is a piece of information that has passed many doctors and patients by, even though the interaction has now been reproduced for other drugs. The effect may be so striking that some scientists are now calling for warning labels about the effects of grapefruit juice on pill bottles to prevent accidental drug overdoses. Others have hastened to patent the chemicals involved and are planning to incorporate them into new combination pills.
"We are harnessing the power of the grapefruit," said Dr. Paul Watkins, a professor of medicine at the University of Michigan in Ann Arbor, whose research recently clarified why grapefruit alone among citrus fruits appears to make some pills more powerful.
The handful of drugs now known to be involved include some common and potent ones, among them Plendil (felodipine) for high blood pressure and heart disease, Seldane (terfenadine) for allergies, Sandimmune (cyclosporine) to prevent rejection of transplanted organs, and Invirase (saquinavir) for treating AIDS.
What these diverse substances have in common is their fate after they pass through the stomach. Unlike other drugs that are absorbed directly from the intestine into the bloodstream, these are first extensively broken down by an enzyme in the wall of the small intestine.
In research published in The Journal of Clinical Investigation in May, Watkins and his colleagues showed that grapefruit juice appeared to remove large amounts of that enzyme from the intestinal wall.
The result is that less of the drug is broken down, more remains in the intestine and more is then absorbed into the bloodstream over a longer period, just as if the patient had actually swallowed a higher drug dose.
The specific causes appear to be chemicals in the juice called furanocoumarins or psoralens that function like "little suicide bombers," attaching to the enzyme and damaging it so badly that the entire complex disappears from the cell.
But the amount of the enzyme in the intestinal wall varies greatly among people, Watkins said, which explains why the grapefruit juice effect may be serious for some people and unimportant for others.
It probably makes very little difference if people with relatively low levels of the intestinal enzyme take their medicine with grapefruit juice or with water. But for others with a great deal of the enzyme, an unaccustomed glass of juice in the morning may send enzyme levels plummeting and drug levels soaring as much as ninefold.
Dr. J. David Spence at the Roberts Research Institute in London, Ontario, thinks this is what may have happened to a Michigan man who died in 1993 with toxic blood levels of Seldane after drinking two glasses of grapefruit juice. "The problem is that juice is taken intermittently," he said. "And grocers don't take a drug history when they sell it."
Seldane blood levels are increased not only by grapefruit juice but also by many common prescription drugs, and serious heart problems may result. Although the drug is under new scrutiny by the Food and Drug Administration for its toxicity, it remains available by prescription in this country and is sold over the counter in Canada.
In new prescribing information supplied to doctors only last month, Seldane's manufacturer, Hoechst-Marion-Roussel, added grapefruit juice to the list of substances that should not be taken with it.
Although information about grapefruit juice accompanies other affected drugs, it is printed in the tiny type reserved for doctors and pharmacists and seldom makes it out onto the patient's pill bottle. Many other drugs have never been specifically tested for grapefruit juice interactions.
The effect of a glass of grapefruit juice on drug levels lasts a day or more, and it increases over time, Spence cautioned. He favors a practice now routine in parts of Australia of affixing specific grapefruit juice warnings to pill bottles if an interaction is known or might be expected.
Other experts feel that chances of drug overdoses from a breakfast containing grapefruit are too small to warrant major public concern.
"These are generally safe drugs," Watkins said. "I just tell patients, if you're used to taking your medicines with juice, keep doing it. If you're not, don't start."
In fact, the danger of grapefruit juice impresses many scientists less than does its ability to augment drug effects cheaply and palatably without the need for larger doses.
Dr. Leslie Benet, chairman of the department of biopharmaceuticals at the University of California at San Francisco, has founded a corporation called Avmax to evaluate and market substances like those in grapefruit juice that inhibit intestinal enzymes, making drugs more available to the body with less person-to-person variability.
His company has licensed one of the patented chemicals responsible for the effect in grapefruit, and is beginning studies combining it with several prescription drugs.
Other doctors just direct patients to the supermarket. Like many doctors who treat AIDS, Dr. Nereida Ferran, an internist at Beth Israel Hospital in New York, routinely advises her patients taking Invirase for HIV infection to take it with grapefruit juice.
"The blood levels of the drug increase at least twofold," she said. "Many of my patients are doing very, very well on what is supposed to be one of the weaker HIV drugs."
And Pizarik remains aware of grapefruit's double-edged potential. Over time, his patient's initially elevated blood pressure dropped so low with grapefruit juice that the man almost went into shock.
"He became pretty pale and pasty-looking," said Pizarik, who has not given grapefruit juice to any other patients. "I don't know that I'd recommend it again until more studies are done."