Excretion Systems

Abstract

AbstractIn previous chapters, the expression and function of metabolic enzymes and drug transporters have been overviewed as important factors dominating ADME (the absorption, disposition, metabolism, and excretion) of drugs. As common features, each metabolic enzyme and transporter consists of a wide variety of isoforms, and the substrate specificity of each isoform is very broad, thereby providing an evolutionary ability to protect the body against numerous kinds of xenobiotics. Thus, a single compound can often be recognized by multiple metabolic enzymes and transporters as a substrate because it partly overlaps with different isoforms of enzymes and transporters. These molecules are appropriately located at several tissues in the body and increase efficiency in the detoxification of xenobiotics. For example, in the liver, efficient detoxification can be achieved by the sequential processing of compounds, such as in the cellular uptake from the blood circulation to hepatocytes via influx transporters, phase I and II metabolism, and biliary excretion via efflux transporters.In this chapter, we present an overview of how combinations of enzymes and transporters work concertedly as a detoxification “system”. Moreover, when evaluating the efficiency of detoxification quantitatively, because these molecules have different roles and do not function in parallel in this system, clearance of xenobiotics in each tissue cannot be expressed simply as the sum or product of an intrinsic clearance of each isoform of metabolic enzymes and transporters. Therefore, we will also discuss theoretical considerations and experimental methods to evaluate the influence of the function of each molecule on the overall efficiency of a detoxification system from the viewpoint of pharmacokinetics.