Transporter, Drug Metabolism, and Drug‐Induced Liver Injury in Marketed Drugs

Drug-induced liver injury continues to be a challenge in drug development. Formation of reactive metabolites from drug metabolism and accumulation of toxic bile acids from disrupted transporters are two proven mechanisms leading to drug-induced liver injury in humans. In this chapter, we introduce the enzymes involved in phase I and phase II drug metabolism and their potential to generate reactive metabolites. We then discuss in silico and experimental approaches to detect and measure reactive metabolites, as well as strategies for reducing the risk of reactive metabolites during drug discovery phase. Finally, we describe hepatic transporters and their relationship with hepatotoxicity. Certain factors, including gene variations, could affect these metabolism enzymes and transporters and determine the susceptibility of individuals. Further investigation of the interactions among the factors from hosts, environment, and drugs will improve our understanding of drug-induced liver injury and mitigate its risk in drug development and clinical practice.