Sometimes drugs you're taking to make you well can end up making you sicker. Carolina researchers are studying ways to personalize dosing to increase drug effectiveness and keep patients safe.

Trouble starts when patients process medicines slower or faster than expected. Genetic makeup, fasting or eating certain foods can affect patients' drug metabolism, said Paul Watkins, professor of medicine and director of the General Clinical Research Center in the School of Medicine. The rates at which people "get rid of" drugs can vary from month to month, or even from week to week, he said.

Watkins has developed and patented a breath test to predict how well patients will metabolize certain drugs. The liver is the main organ that processes drugs, and because liver function is often measured using a breath test, he said, it seemed logical to measure drug metabolism the same way.

In a recent study, Watkins' erythromycin breath test accurately predicted how well 22 patients would metabolize the chemotherapy drug docetaxel.

"Because people metabolize drugs differently, the recommended dose of many chemotherapies will make about 10 percent of patients very ill, and 1 or 2 percent of patients may actually die as a direct result of the treatment," he said. Other patients who process a chemotherapy treatment faster than expected may not get a dose that's strong enough to fight their cancer.

Watkins' test measures the amount of carbon dioxide emitted in a patient's breath after taking a trace dose of the antibiotic erythromycin.

Erythromycin is metabolized by the same enzyme in the liver -- Cytochrome P4503A4 -- that metabolizes docetaxel and many other drugs. Carbon dioxide is the main byproduct produced when the liver processes erythromycin.

To "label" the carbon dioxide that results from metabolizing the drug, as opposed to the carbon dioxide that everyone normally breathes out, a single radioactive carbon atom is added to the erythromycin. The total radiation exposure is about one-tenth that of a chest X-ray, Watkins said.

"We found that measuring the radioactive carbon dioxide in patients' breath 20 minutes after they take the erythromycin tells you everything you want to know," Watkins said.

A high level of carbon dioxide would mean that the patient was metabolizing the drug quickly, while a low score would show that the liver was eliminating the drug more slowly.

After the breath test, researchers gave patients the normal doses of docetaxel and used blood tests to measure its levels in their bodies. The researchers didn't know the results of the breath tests until after the study was over.

The breath-test results matched those from the blood tests. And they jibed with the patients' response to the chemotherapy. Two patients grew ill from the standard dose of docetaxel and had to be hospitalized.

"They became very toxic from the drug, even though they got the same dose as everybody else," Watkins said.

At the end of the study, the researchers found that these two patients had scored lowest on the breath tests, meaning that they metabolized docetaxel more slowly.

Other researchers are using the test to further study drug metabolism. Stan Carson, associate professor of pharmacy, is using it to study whether St. John's Wort affects Cytochrome P4503A4's ability to metabolize other drugs. Some patients with chronic diseases take St. John's to ward off depression or anxiety, Carson said, so it's important to know if the herb affects drugs the patients are taking to treat their diseases.

In his study, Carson gave patients the breath test, which showed how fast they metabolized the trace amount of erythromycin. Then they took St. John's Wort for two weeks and took the breath test again. Preliminary results show St. John's Wort significantly increases cytochrome P4503A4 metabolism.

Another study used the breath test to try to determine what enzyme metabolizes quinine, a drug used to treat and prevent malaria.

Watkins conducted the study at Carolina with his colleague, Sampon Wanwimilruk, from the University of Otaga in New Zealand. Since people seem to metabolize quinine at many different rates, Wanwimilruk thought that maybe Cytochrome P4503A4 was the main enzyme that does the job.

Using the breath test, he found that while Cytochrome P4503A4 is a significant enzyme in metabolizing quinine, it isn't the major enzyme. So the breath test probably can't be used for dosing quinine.

"He's gone back to the drawing board and is looking for other enzymes," Watkins said.