The role of drug metabolizing enzymes in clearance.

INTRODUCTION: Metabolism is one of the most important clearance pathways representing the major clearance route of 75% drugs. The four most common drug metabolizing enzymes (DME) that contribute significantly to elimination pathways of new chemical entities are cytochrome P450s, UDP-glucuronosyltransferases, aldehyde oxidase and sulfotransferases. Accurate prediction of human in vivo clearance by these enzymes, using both in vitro and in vivo tools, is critical for the success of drug candidates in human translation. AREAS COVERED: Important recent advances of key DME are reviewed and highlighted in the following areas: major isoforms, tissue distribution, generic polymorphism, substrate specificity, species differences, mechanism of catalysis, in vitro-in vivo extrapolation and the importance of using optimal assay conditions and relevant animal models. EXPERT OPINION: Understanding the clearance mechanism of a compound is the first step toward successful prediction of human clearance. It is critical to apply appropriate in vitro and in vivo methodologies and physiologically based models in human translation. While high-confidence prediction for P450-mediated clearance has been achieved, the accuracy of human clearance prediction is significantly lower for other enzyme classes. More accurate predictive methods and models are being developed to address these challenges.