Vanderbilt Doctors Find Citrus Soda Interacts With Cyclosporine, Maybe Statins

It took a team of medical sleuths at Vanderbilt University Medical Center to discover that the wild up-and-down swings in levels of the anti-rejection drug cyclosporine were fueled by the Sun Drop soft drink Turner drank to quench his caffeine cravings. Solving the case identified a new food-and-drug interaction that could be harmful for all transplant patients, and, possibly, people taking a class of anti-cholesterol drugs called statins.

During a clinic visit to Aaron Milstone, M.D., assistant professor of Medicine and medical director of Vanderbilt's Lung Transplant Program, Turner's blood was drawn to monitor, among other things, the serum levels of the drug cyclosporine, which kept his body from rejecting his new organs. The levels, previously normal, were more than double the suggested concentration, creating the potential for drug toxicity and serious side effects, such as kidney damage or central nervous system damage.

The question was, why.

Milstone and transplant coordinator Haley Hoy questioned Turner extensively about the possibility of altered cyclosporine doses or any other changes in his new medical routine. Turner said he felt fatigued and was experiencing nervous tremors, but had done nothing different.

Turner was tested again two days later and his cyclosporine serum levels were well within therapeutic limits. This pattern repeated itself again at the next month's clinic visit: the cyclosporine levels were more than twice the accepted level on the day of the clinic visit, but then normal again upon retesting two days later.

"After this process of high and normal levels repeated itself, we began a dietary inquiry," Milstone said. "Is there something in Bill's diet that was doing this?"

Milstone says all transplant patients are counseled not to consume grapefruits or Mediterranean oranges because those citrus products contain a compound, called bergamottin (pronounced bur-GA-mot-tin), that blocks metabolism of certain medications in the liver, particularly cyclosporine.

Over a period of several weeks, Turner and Hoy carefully went over everything Turner was eating or drinking hoping for a clue. "We really struggled with this," Hoy said.

"I started thinking about strange things in my diet," Turner said. "That's when I thought about Sun Drop. Since it's a citrus soda I wondered if it had grapefruits in it."

Sun Drop is a popular citrus soft drink, introduced in 1951, that according to the corporate Web site of Texas-based Dr Pepper/7Up, Inc. (Sun Drop's parent corporation), is the nation's seven-time sales leader in the citrus soda category. Sun Drop is sold throughout the South Atlantic region of the United States.

Suspecting Turner's hunch about his source of caffeine was correct, Milstone contacted Philip Johnston, Pharm.D., assistant director of Vanderbilt Pharmaceutical Services, for help solving the mystery.

Johnston, well aware of the effect of citrus products on the metabolism of certain drugs, began a circuitous pursuit of the beverage's basic ingredient information from Sun Drop's corporate parent.

"We thought there was something significant about this, and we needed to check with the bottler," Johnston said. "We found the bottler in Tullahoma, Tenn. from Tullahoma we were referred to the corporate headquarters in Dallas, and from there we were referred to a customer service division in St. Louis. We sent a formal letter to a customer service representative, who in turn delivered the letter to someone in their formulation division.

"We didn't expect them to give us their formula, that's a trade secret. But we were very interested in whether the beverage had a bergamottin component. After several days, and another phone call, the company responded by e-mail saying that Sun Drop contains the type of ingredient you refer to in your letter."

Johnston says the admission was enough to convince him and Milstone of the cause of Turner's high cyclosporine levels. Mystery solved, ride over.

Both say a formal study is needed to examine the extent of the effects of Sun Drop, and a growing number of other drinks containing citrus products, on the disruption of excretion and absorption of cyclosporine and certain other prescription drugs.

Although there isn't a body of published evidence yet, there is strong evidence to suggest beverages containing bergamottin also alter the absorption and excretion of statins (HMG-CoA reductase inhibitors), which would affect a high percentage of the U.S. population on this class of drugs.

Johnston and Milstone have submitted an article for publication in the journal Transplantation regarding the effect of Sun Drop on cyclosporine levels, suggesting that such citrus-containing products be labeled to include this information.

Turner, who has recovered completely from the ordeal and is doing well, is a bit humble about his discovery, its potential benefit to transplant patients and to all those taking cholesterol-lowering drugs.

"I guess it's good for transplant patients to know about Sun Drop,'" he said. "I would hope this might make food and beverage manufacturers think about the way products are labeled, and hopefully provide better labeling with appropriate cautions for people."