Researchers first discovered that grapefruit juice can alter drug disposition nearly twenty years ago, and it has taken scientists since then to fully understand the mechanisms and active ingredients underlying these interactions.

Now, as focus shifts to potential drug interactions with other fruit juices, Mary Paine, PhD, hopes to help streamline the process of identifying drug-diet interactions.

Paine, an assistant professor in the Division of Pharmacotherapy and Experimental Therapeutics, has teamed up with Nicholas Oberlies, PhD, director of the Natural Products Laboratory at Research Triangle Institute, to evaluate interactions between drugs and dietary substances. Paine hopes that by merging drug metabolism research with natural products research, they will be able to identify and understand drug interactions more efficiently and economically.

“We know a great deal about drug-drug interactions but comparatively little about how foods and other natural products interact with drugs,” Paine says. “Typically, the only thing patients are told about food and their medicine is whether or not they should take their pills with a meal.”

In 2007, Paine received an NIH grant for her project, titled “Mechanisms Underlying Drug-Diet Interactions.” The grant is worth more than $300,000 a year and is renewable for up to four years.

To date, most of Paine’s research has centered on cranberry juice, one of her personal favorites and a food that has received attention in recent years for a potential interaction with the anticoagulant warfarin.

“Cranberry juice has been shown to prevent urinary tract infection, and many people—especially women—drink the juice for that reason,” Paine says. “As we argued in the grant, the incidence of cranberry juice consumption in combination with drugs could be high in certain segments of the population who could be at increased risk of untoward effects.”

Several case reports in the United States and the United Kingdom have shown possible interactions between cranberry juice and warfarin. The reports were enough for the UK Committee on Safety of Medicines to issue a warning advising patients taking warfarin to avoid drinking cranberry juice or other cranberry products. The US Food and Drug Administration also issued a warning stating that patients who take warfarin should avoid cranberry products.

“All of this has been done when there is still no convincing evidence that there is or is not an interaction potential,” Paine says.

A 2006 study conducted by researchers at Tufts University School of Medicine and Tufts-New England Medical Center found no evidence of a link between cranberry juice and warfarin. Their study used a metabolic surrogate for warfarin, an anti-inflammatory drug called flurbiprofen, which is metabolized by CYP2C9, the same enzyme that metabolizes warfarin. A later study by a Finnish group also found no interaction.

Paine is focusing on a different enzyme involved in drug metabolism CYP3A, the same enzyme inhibited by grapefruit juice. Unlike CYP2C9, which metabolizes in the liver, CYP3A also metabolizes in the small intestine, which Paine says is where the juice/enzyme interaction occurs.

The Finnish group that previously examined CYP2C9 and warfarin had also looked at CYP3A and a short-acting hypnotic agent called midazolam, but they identified no interaction in the brand of cranberry juice they tested. Instead of using just one variety of cranberry juice, Paine first tested five brands for their inhibitory activity toward intestinal CYP3A in vitro.

After identifying the most potent juice, Paine moved on to an in vivo study involving sixteen healthy volunteers. Participants were given midazolam with water on one occasion and with the selected cranberry juice on another. Paine says that the initial results indicate a significant inhibition of intestinal metabolism when the cranberry juice was taken.

“We contend that the juice we tested contained sufficient concentrations of the inhibitory ingredients to elicit an effect in vivo, whereas the juice used by the [Finnish] group (who did not do any a priori in vitro testing) had insufficient concentrations,” Paine says.

After establishing that there is a cranberry-juice effect, Paine and Oberlies hope to identify the active ingredients in cranberry juice that cause the interaction. To do that, Paine anticipates looking at a number of brands of cranberry juice, and she says there may be different contributing variables in the different brands. She hopes the research will ultimately help medical professionals give informed advice to patients.

“The literature on cranberry juice/drug interactions is conflicting,” Paine says. “Some studies say there are no interactions and some say there are, so what do pharmacists and doctors tell their patients? We want to give them the answer of whether patients should be taking the drugs with the juice or not.”

Paine isn’t limiting her research to cranberry juice. She’s also looking at the drug interaction potential of pomegranate juice, an increasingly popular juice that has been shown to have chemopreventive properties.