Pharmacogenomics Applications in Drug Metabolism: From Genotyping to Drug Label-Challenges

There is increasing recognition that pharmacogenetic polymorphisms affecting drug metabolism are valid biomarkers affecting drug safety and efficacy. This is shown by the inclusion of information about genetic polymorphisms affecting drug metabolism on drug labels with, in some cases, a recommendation that testing for the polymorphism should be performed before prescription. However, in most cases, this information is for information only. It is likely that this is in part because testing for the relevant polymorphisms is unlikely to be available to patients being prescribed the drug, but also because clear advice about issues such as dose adjustment is not available, mainly since appropriate clinical trials have not yet been performed. Metabolic polymorphisms mentioned by the U.S. Food and Drug Administration (FDA) as valid biomarkers include those in thiopurine methyltransferase, the UDP-glucuronosyltransferase UGT1A1, the cytochromes P450 CYP2D6, CYP2C19, and CYP2C9, the N-acetyltransferase NAT2, and dihy-dropyrimidine dehydrogenase. Each of the above polymorphisms is considered here in detail, with particular reference to current knowledge and to their relevance to the drugs considered to be related to the individual polymorphisms.