Active metabolites in drug development

It is almost a decade since the second edition of the Handbook of Drug Metabolism was published. Since its inception, the goal of the Handbook was to provide a comprehensive text to serve as a graduate course in Drug Metabolism, a useful reference for academic and industrial drug metabolism scientists, but also as an important reference tool for those pursuing a career in drug discovery and development. The third edition of the Handbook of Drug Metabolism has been markedly updated to capture a decade of advances in our understanding of factors that impact the pharmacokinetics and metabolism of therapeutic agents in humans. Moreover, we have sought to include new chapters that reflect significant advances that have occurred in major areas viz., the role transporters in drug disposition, active metabolites in drug development, predicting clinical pharmacokinetics, nonP450 biotransformation reactions, pharmacogenetics in drug metabolism and toxicity, drug interactions, and antibody drug conjugates.

The third edition of the Handbook of Drug Metabolism is organized into four sections. The first three sections capture scientific and experimental concepts around drug metabolism. Section I reviews fundamental aspects of drug metabolism, including a history of drug metabolism, a review of oxidative and non-oxidative biotransformation mechanisms, a review of liver structure, and function and pharmacokinetics of drugs metabolites. Section II details factors that impact drug metabolism, including pharmacogenetics, drug-drug interactions, and the role of extra-hepatic organs in drug biotransformation. Section III provides in depth insights into analytical technologies and methodologies to study drug metabolism at the molecular, subcellular, and cellular levels, and considerations of factors, viz. enzyme inhibition and induction that influence drug metabolism and therapeutic response. Section IV has been expanded substantially from the second edition to illustrate the highly integrated role of drug metabolism in drug discovery and drug development. In this regard, Section IV focuses on clinical and preclinical drug metabolism studies, safety considerations for drug metabolites (chemically-reactive and non-reactive metabolites) in the selection and development of promising therapeutic candidates and highlights the increased focus of regulatory agencies on safety considerations of drug metabolites. The discipline of drug metabolism is now a highly integrated component of contemporary drug discovery and development programs—the results of these efforts have lead to only a small number of clinical development candidates that fail in clinical development for unacceptable pharmacokinetic and drug metabolism properties.

In: Handbook of drug metabolism. 3rd ed. Pearson PG, Wienkers LC, editors. Boca Raton: CRC Press; 2019. Chapter 24; p.27. 750p.