Pharmacogenetics is a blossoming area of research aimed at connecting a person's genetic make-up with his or her response to medicines. As drugs move through the body, they interact with thousands of molecules called proteins, each encoded by a different gene. Because each person is genetically unique, tiny differences in these proteins can affect how medicines do their jobs in the body, since some of these proteins work to get rid of medicines, while others help medicines do their jobs. For example, certain drugs used to treat cancer can have widely variable effects in patients, and many of these treatments have serious toxicities. On occasion, patients are literally poisoned because their bodies cannot get rid of, or "clear," cancer treatments in a timely manner. Patients given an identical dose of the commonly used chemotherapy drug Taxotere (docetaxel), for instance, display wide variation in the amount of time it takes their bodies to clear this medicine. Scientists have suspected that gene differences may account for at least some of the variability in response to docetaxel.
Now, Dr. Paul Watkins at the University of North Carolina at Chapel Hill has confirmed this suspicion using a simple "breath test" that measures an individual patient's ability to break down docetaxel. Several years ago, Watkins and his coworkers came up with the idea for the breath test, which measures the strength of a drug-metabolizing protein nicknamed "CYP3A4." The CYP3A4 protein chews up many different drugs, including the antibiotic erythromycin. Researchers use the breath test to gauge patient's CYP3A4 activity by injecting a tiny amount of erythromycin containing trace levels of the radioisotope 14C, and then measuring the amount of radioactive carbon dioxide the patient exhales 20 minutes later. (The very small amount of radioactivity poses no danger to the patient or health care provider.) In a small clinical study, Watkins and his team successfully used the breath test to track patients' breakdown of docetaxel. Underscoring the predictive value of the simple test, the scientists found that the patients with the lowest scores on the breath test were the ones who suffered the greatest docetaxel toxicity.
Watkins' new work introduces an important potential role for the breath test in predicting toxicity caused by a widely used cancer drug. Since many medicines are metabolized by the CYP3A4 protein, the breath test may prove useful in the clinic as a rapid and easy way to predict individual patients' responses to other drugs. Since previous blood tests failed to predict docetaxel toxicity ahead of time, the breath test may offer a promising tool to help physicians administer this drug more safely. Makers of the breath test are currently seeking FDA approval--a step that will mark another practical use of pharmacogenetics in the clinic.
REFERENCE
Hirth J, Watkins PB, Strawderman M, Schott A, Bruno R, and Baker LH. The effect of an individual's cytochrome CYP3A4 activity on docetaxel clearance. Clin. Cancer Research 2000;6:1255-8.
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