The evolving role of drug metabolism in drug discovery and development

Drug metabolism in pharmaceutical research has traditionally focused on the well-defined aspects of absorption, distribution, metabolism and excretion, commonly-referred to ADME properties of a compound, particularly in the areas of metabolite identification, identification of drug metabolizing enzymes (DMEs) and associated metabolic pathways, and reaction mechanisms. This traditional emphasis was in part due to the limited scope of understanding and the unavailability of in vitro and in vivo tools with which to evaluate more complex properties and processes. However, advances over the past decade in separate but related fields such as pharmacogenetics, pharmacogenomics and drug transporters, have dramatically shifted the drug metabolism paradigm. For example, knowledge of the genetics and genomics of DMEs allows us to better understand and predict enzyme regulation and its effects on exogenous (pharmacokinetics) and endogenous pathways as well as biochemical processes (pharmacology). Advances in the transporter area have provided unprecedented insights into the role of transporter proteins in absorption, distribution, metabolism and excretion of drugs and their consequences with respect to clinical drug-drug and drug-endogenous substance interactions, toxicity and interindividual variability in pharmacokinetics. It is therefore essential that individuals involved in modern pharmaceutical research embrace a fully integrated approach and understanding of drug metabolism as is currently practiced. The intent of this review is to reexamine drug metabolism with respect to the traditional as well as current practices, with particular emphasis on the critical aspects of integrating chemistry and biology in the interpretation and application of metabolism data in pharmaceutical research.