Chapter 11 - Metabolic Stability

Abstract

This chapter focuses on metabolic stability, which is widely considered one of the most significant challenges of drug discovery. Drugs encounter formidable challenges to their stability in vivo. An overview of in vivo stability challenges suggests a diverse ensemble of chemical and enzymatic reactions poised to attack various moieties of the molecule. Drug metabolism often is referred to as biotransformation, and metabolism reactions have been divided into two phases. Phase I reactions are modifications of the molecular structure itself, such as oxidation or dealkylation. Phase II reactions are additions (conjugations) of polar groups to the molecular structure. Several strategies for increasing the metabolic stability of compounds have been successful. Metabolic stability plays a major role in drug clearance. It is commonly measured in vitro during drug discovery as soon as a new compound is synthesized. This provides feedback that alerts the project team to metabolic limitations and provides data to guide metabolic stability improvement through structural modifications. The crucial nature of metabolic stability and the relatively low cost of in vitro stability assays can be leveraged to assist with more expensive processes in discovery.