newsmakers: Safer Doses are a Breath Away
	by Angela Spivey

f all goes well, a simple breath test could save lives.

Researchers found that the erythromycin breath test accurately predicted how well 22 patients would metabolize the chemotherapy drug docetaxel. Standard doses of such drugs can kill people who don’t process them at the expected rate.

Paul Watkins, professor of medicine and director of the General Clinical Research Center in the School of Medicine, developed and patented the test. Such a test is needed, he says, because the rates at which people “get rid of” drugs can vary from month to month, or even from week to week.

“Some people think that genetic information will tell the physician everything he needs to know about what drugs and what doses to give people,” Watkins says. “But your genes are only one important part of the story.” Weight loss and lack of appetite—common in cancer patients—can dramatically affect drug metabolism. So can some common foods. Watkins did some of the first research that showed how grapefruit juice significantly affects certain types of drugs.

Watkins’ test measures the amount of carbon dioxide emitted in a patient’s breath after taking a small 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 these drugs.

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 says.

“We found that measuring the radioactive carbon dioxide in patients’ breath twenty minutes after they take the erythromycin tells you everything you want to know,” Watkins says. 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.

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

Watkins and his colleagues are investigating the test further. Stan Carson, associate professor of pharmacy, is using it to study how St. John’s Wort affects cytochrome P4503A4’s ability to metabolize other drugs. Another Carolina study, almost completed, is investigating whether the test can be used to predict how patients will metabolize a malaria drug. Watkin’s colleague and study coauthor, Laurence Baker of the University of Michigan, is halfway through a study that uses the test to actually adjust patients’ chemotherapy dose levels. So far the patients are doing well, and none have been hospitalized because of side effects.

“He’s finding that these patients’ response rates to chemotherapy are much better than you would otherwise expect,” Watkins says.

A report on this research appeared in the April issue of Clinical Cancer Research. Besides Watkins and Baker, study authors are JoAnn Hirth, Myla Strawerman, and Anne Schott, all of the University of Michigan. The test is available for research use only from Metabolic Solutions, Inc., in New Hampshire.

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