Genetically Determined Polymorphisms in Drug Metabolism

Many factors can influence the metabolism and disposition of drugs. Genetically determined differences in an individual's capacity to metabolize drugs are known causes of interindividual and interethnic variabilities in drug disposition and response. In general, a poor metabolizer for a specific metabolic pathway would likely develop adverse effects, and an extensive metabolizer for the same metabolic pathway might have less than optimal response. Although there are different types of polymorphism in drug metabolism, polymorphisms in debrisoquine-type oxidation, S-mephenytoin oxidation, and N-acetylation have been the most extensively studied. This article will present the basic concepts of pharmacogenetics, review the major types of metabolic polymorphisms, outline ways to determine phenotyping and genotyping differences in metabolizing enzyme activities, and discuss how these differences relate to drug metabolism, response, and toxicity. When evaluating drug response and adverse reactions in individual patients, an awareness of genetic differences in metabolic capacities would help contribute to optimization in drug therapy.