About six years ago, Canadian researchers discovered quite by accident that people who sloshed down their high blood pressure medicine with a glass of grapefruit juice got an extra kick: The drug became much more effective, apparently because it was absorbed better by the body.
So much more effective, in fact, that some doctors now worry that people who usually use water to take certain calcium channel blockers may wind up lowering their blood pressure too steeply if they suddenly switch to grapefruit juice.
Then there’s the case of the young Michigan man who reportedly died of cardiac arrythmia soon after taking Seldane, the antihistamine/decongestant, with two glasses of grapefruit juice.
“The cause of his death is that he took Seldane with grapefruit juice,” says Dr. J. David Spence, one of the Canadian researchers and director of stroke prevention and atherosclerosis research at the Robarts Research Institute in London, Ontario.
But others, among them Dr. David Flockhart, associate director of the division of clinical pharmacology at Georgetown University Medical Center in Washington, D.C., say that after two studies on Seldane and grapefruit juice, the evidence remains inconclusive.
Nonetheless, Hoechst Marion Roussel, the manufacturer of Seldane, added a warning to package labels in May advising people not to take the pill with grapefruit.
Who’d-a-thunk it? Good old grapefruit, that mouth-zinging staple of many a breakfast table, cast in the role of nutritional bad guy!
Yet the “grapefruit effect” has been a source of concern for several years now, and two weeks ago University of Michigan researchers said they had discovered the reason why.
Unlike oranges and other citrus fruits, grapefruit — both in juice form and in wedges — contains two types of chemicals called furanocoumarins, says Dr. Paul B. Watkins, director of the University of Michigan General Clinical Research Center in Ann Arbor.
These substances trigger the drug-potentiating effect by interacting with an enzyme (called CYP3A4) in the intestinal walls. Normally, this enzyme breaks down some, though not all, drugs as they pass through the digestive system, says Watkins, adding that this is actually a problem for drug manufacturers because the enzyme makes it tough to get adequate quantities of some medications into the bloodstream.
But when grapefruit juice is present — and some researchers think its effects can linger for a day or more — the enzyme is knocked out of commission and absorption of certain drugs is dramatically increased, sometimes by as much as nine times.
With the immunosuppressant cyclosporin, for instance, grapefruit juice boosts absorption so much that some patients who take the drug to prevent rejection of a transplanted organ can get the same effect with less medication.
Dr. Ray Woosley, chairman of the pharmacology department and co-director of the Cardiovascular Institute at Georgetown, says that when his brother, a kidney transplant patient, began taking grapefruit juice along with cyclosporin, he was able to cut the cost of his medication from $12,000 a year to $6,000.
Donna Surratt, a 52-year-old liver transplant recipient from Forestville, Md., says that when she started taking grapefruit juice along with the immunosuppressant FK-506, the juice boosted the drug’s effect so much doctors became concerned about toxicity.
Some AIDS patients, too, use grapefruit juice to boost the absorption of drugs, notably saquinavir, a protease inhibitor.
But Dr. Greg Robbins, an infectious disease specialist at Massachusetts General Hospital, urges caution, warning that doctors don’t know enough about the interaction of grapefruit juice and AIDS drugs. A better-documented way to boost saquinavir’s effectiveness, he says, is to add a second protease inhibitor, ritonavir.
Dr. Jerome Groopman, an AIDS specialist and chief of experimental medicine at Beth Israel Deaconess Medical Center, adds that a just-released formulation of saquinavir is much better absorbed than its predecessor and that in general patients should not try to boost drug effects with grapefruit juice without checking with a doctor or druggist.
Flockhart of Georgetown agrees, noting that one of his patients “went close to psychotic” after taking grapefruit juice with a morphine-based painkiller called MS Contin.
Flockhart, who has compiled a list of drugs that may interact with grapefruit juice, also warns about mixing grapefruit with the sleeping pill Halcion or the sedative Xanax.
A number of calcium channel blockers, taken to lower blood pressure, also appear to interact with grapefruit juice, says Watkins of Michigan, though the degree of effect varies greatly. One such drug, Sular, now comes with a warning against taking it with grapefruit.
Cholesterol-lowering drugs such as lovastatin and simvastatin, as well as a drug called Propulsid for gastrointestinal reflux, may interact with grapefruit juice, too, although this is not as well studied.
So far, none of this constitutes a huge public health concern, says Watkins, because many drugs are designed to be safe even at high blood levels. This is especially true for drugs whose absorption rates vary.
Still, it gets tricky trying to figure out just how much grapefruit juice may affect drug metabolism in a given patient. Part of the difficulty is that the quantity of active ingredients in grapefruit varies considerably — between grapefruit products and even between different lots of the same brand of frozen concentrate.
Furthermore, people vary widely in how much of the intestinal enzyme they produce.
“If you have a lot of this enzyme,” says Watkins, “you won’t get much of certain drugs into your body. Therefore, taking grapefruit juice will have a big effect. If you have low amounts of this enzyme, you will already be absorbing higher amounts of drugs, and grapefruit juice will add little effect.” Unfortunately, there is no easy way consumers can gauge their enzyme levels.
Among those increasingly fascinated by the grapefruit effect are drug manufacturers, some of whom are now trying to incorporate the active ingredients into various pills, says Watkins, who consults with drug companies and is chairman of the scientific advisory board at AvMax, Inc. in Berkeley, Calif.
The ideal targets are pills that are poorly absorbed by the body in their current form, adds Jeff Silverman, an experimental pathologist at AvMax.
So what should you do until the scientists sort it all out?
The safest course is to not change what you’re doing. If you have been taking your pills with grapefruit juice for years and have had no problems, keep on doing so. If you haven’t, don’t start.
If you’re curious about a particular combination, ask your pharmacist to look up potential interactions.
And you can follow the rule of thumb some grapefruit researchers have come up with: If a drug carries a warning of possible adverse interaction with the antibiotic erythromycin, there’s a decent chance it interacts with grapefruit, too.
In other words, if you shouldn’t combine a particular medication with erythromycin, don’t take it with grapefruit juice, either.