Role of Biotransformation in Drug Discovery

Biotransformation is important in the drug discovery process because several aspects of the clinical profile of a drug candidate depend on the process of biotransformation. Clearance of a drug from the body most often involves biotransformation, so the quantitative rate of clearance may be modulated by modification of the chemical structure to increase or decrease the rate of metabolism. Clearance also involves the qualitative process of chemical transformation of the parent drug to yield metabolites which may have their own pharmacological or toxicological characteristics. Both the quantitative and qualitative aspects of clearance require knowledge of the chemical structures of the metabolites to be used by medicinal chemists to intelligently design subsequent analogs in optimizing the druglike profile of a series of discovery candidates. The type of metabolite produced often tells the type of metabolic enzyme that was involved, which provides information about the expected clinical characteristics such as likely drug interactions, genetic variability, and inducibility. Several functions of discovery-level biotransformation are not yet adequate for the purpose, especially real-time identification of metabolites during metabolic stability screening and determination of the chemical process leading to metabolism-based inhibition (MBI) of CYP enzymes.