Oct. 1, 2013 The discovery of genetic differences affecting up to a third of the population could take the guesswork out of prescribing the correct dose of 25 percent of drugs currently on the market, researchers say.
The scientists found two genetic variants that alter the activity level of an enzyme responsible for processing, or metabolizing, drugs ranging from the painkiller codeine to the breast cancer drug tamoxifen.
The Ohio State University researchers who found these differences say that pending additional research, the variants are good candidates for inclusion in an existing biomarker test that guides drug dosing.
The current test is designed to determine the enzyme's activity level, or expression, to predict whether a patient will fall into one of four categories: poor, intermediate, extensive or ultra-rapid metabolizer. Metabolism speed affects how much medicine a patient needs.
But there are limits to the existing test: The current biomarker panel is based on variants that have been associated with how patients respond to different doses of drugs.
The researchers who found these previously unidentified variants, however, have determined the specific effects that the variants have on drug metabolism. One reduces the enzyme's activity twofold by turning off a function of its gene, and the other is located in an enhancer region of the gene, meaning it increases the enzyme's expression between two- and fourfold.
"If you don't consider these two variants, the current biomarker panel can cause incorrect dosing," said senior author Wolfgang Sadee, professor and chair of pharmacology and director of the Center for Pharmacogenomics at Ohio State. "The better the test, the more value it has. Adding these variants to the panel would make the test more predictive and robust with respect to application in the clinic."
Ohio State has applied for a patent on the addition of these variants to a clinical biomarker test.
The research is published online in the journal Human Molecular Genetics.
The study included a clinical trial of 164 children, about one-third of whom were African American. The results show that these two variants are common in both Caucasians and African Americans, and confirmed that the variants influence how patients metabolize the cough suppressant dextromethorphan.
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New genetic discovery could reduce the guess work in drug dosing