Metabolism: Principle, Methods, and Applications

Drug metabolism is divided into three phases: phase I (mainly oxidation), phase II (conjugation), and phase III (transport/elimination). This chapter discusses the role of these three phases in the disposition of drugs and of drug‐metabolizing enzymes (DMEs) in metabolic clearance, renal clearance, or hepatic clearance. Drug metabolism has critical impacts on (1) clearance of drug from the body; (2) pharmacological activity due to exposure; (3) toxicity due to accumulation or metabolite formed; and (4) extent of drug–drug interaction (DDIs). The species differences in drug metabolism by DMEs phase I, II, and III between animal species and humans are common and frequently complicate preclinical drug development programs. There are various in vitro, in vivo, and in silico models that are often employed throughout drug discovery and development. The purpose of each model system is to provide necessary information to elucidate the metabolic disposition of new and existing drug molecules.