The Role Of Biotransformation Studies In Reducing Drug Attrition

Biotransformation has evolved beyond simple structural elucidation of metabolites to provide data that is highly impactfuland influential to various aspects of drug discovery. Based on our experience, we have grouped areas where biotransformation-related understanding can make an impact on drug design as follows: (1) defining clearance mechanisms, particularly for drug metabolizing enzymes other than P450s, (2) identifyingmetabolic hot spots, (3) identifying reactive metabolites, (4) characterizing active metabolites, and (5) assessing metabolite safety. This review will describe how these studies may be used to guide the development of structure-activity relationships to identify and mitigate potential safety liabilities and to interpret pharmacokinetic/pharmacodynamic (PKPD) relationships. Ultimately, a better understanding in all these aspects of drug disposition will aid in reducing candidate attrition.