Culprit in Grapefruit Juice Drug Interaction Identified

Over 15 years ago, researchers uncovered a dangerous interaction between grapefruit juice and certain medications when they gave volunteers grapefruit juice to mask the taste of a medication. Now, scientists have identified the ingredients responsible, which may enable manufacturers to create a grapefruit juice that doesn’t have the same effect.

After the discovery of the grapefruit juice effect, NIH-funded researchers identified a prominent enzyme called CYP3A4 as the juice’s target. CYP3A4 is found in the cells that line the small intestine and helps break down about half of all marketed drugs. Grapefruit juice inhibits this enzyme, causing more of the drugs to enter the blood stream and effectively resulting in doses that are too strong.

Researchers originally thought that compounds called flavonoids were responsible because they’re present in high concentrations in grapefruit juice and were shown to inhibit CYP3A4 in laboratory experiments. When purified flavonoids were tested in humans, however, they didn’t show the same effect. Two of another class of chemicals called furanocoumarins are abundant in grapefruit juice and also inhibited CYP3A4 in laboratory tests. Human studies showed that while those two chemicals do have an effect in the body, they don’t account for the full effect of the juice.

A team of researchers funded by NIH and led by Paul B Watkins at the University of North Carolina at Chapel School of Medicine used a method to remove nearly all of the different types of furanocoumarins from grapefruit juice to test the idea that furanocoumarins really are responsible for the grapefruit juice effect. They compared the modified grapefruit juice with orange juice, which has little effect on CYP3A4, and with unaltered grapefruit juice.

In the May issue of the American Journal of Clinical Nutrition, the researchers report that removing furanocoumarins from grapefruit juice took away its drug-altering effects. The scientists gave 18 healthy volunteers one of the three juices along with 10 milligrams of felodipine, a blood-pressure drug known to interact with grapefruit juice. Their blood was collected over 24 hours to measure felodipine levels. In contrast to those who drank unaltered grapefruit juice, the people who drank furanocoumarin-free grapefruit juice had blood levels of felodipine similar to those who’d had the orange juice.

The food-grade methods the researchers used can potentially be used to make furanocoumarin-free grapefruit juice commercially. Knowing the compounds responsible for these drug interactions has other benefits, too. It can now help scientists spot potential drug interactions in other foods. These compounds might even be used in medications one day to enhance their effectiveness.