Deciphering the grapefruit juice effect.

Some dozen different studies have shown that drinking grapefruit juice appears to increase markedly the potency of several commonly prescribed drugs, including sedatives and medicines for high blood pressure. There have even been reports of patients who unwittingly overdosed when they used the citrus libation to wash down a prescribed pill.

Researchers have now traced grapefruit's effect to a decrease in a critical drug-degrading enzyme in the small intestine, they report in the May 15 Journal of Clinical Investigation.

The components of the juice that suppress this enzyme, known as CYP3A4, remain unknown. If identified, however, they might be added to certain drugs to lower the effective doses, says gastroenterologist Kenneth S. Lown of the University of Michigan Medical School in Ann Arbor. Indeed, notes Lown, who led the study, because this enzyme plays a role in "metabolizing one out of every three drugs," the unexpected finding could have broad applications.

His team admitted 10 healthy men to a hospital for a 12-day trial. Each volunteer was put on a diet entirely devoid of fruits and vegetables. Beginning on day 6, the men received 8 ounces of grapefruit juice with each meal.

The scientists already suspected that this juice worked by inhibiting Vie ability of CYP3A4 to break down drugs, but because the body often compensates by ratcheting up its production of an affected enzyme, they expected the grapefruit effect to diminish with each succeeding glass of the juice.

To "our shock," Lown observes, the opposite occurred.

On days 4, 6, and 11, each man took 10 milligrams of felodipine, an antihypertensive drug whose effect is enhanced by the juice (SN: 2/9/91, p. 85). When the pill was swallowed after the first glass of juice, concentrations of the drug in each man's blood more than tripled over those measured 2 days earlier. By day 11, and the men's 16th glass of juice, drug concentrations had climbed to more than four times the initial values. Moreover, though intestinal amounts of CYP3A4 initially varied widely among the men, after 6 days of drinking the juice, all exhibited similar low enzyme concentrations--and should reflect an equal response to the drug.