HIGH THROUGHPUT ASSAYS FOR DRUG GLUCURONIDATION

Drug metabolism problems such as production of toxic metabolites and unfavorable pharmacokinetics cause almost half of all drug candidate failures during clinical trials. Although glucuronidation is one of the most important routes of drug metabolism, the broad and overlapping substrate specificity of the hepatic UDP-glucuronosyltransferases (UGTs) that catalyze glucuronidation remains poorly understood. Thus, pharmaceutical companies have an immediate need for better methods to determine whether their potential drug candidates will be glucuronidated, and if so by which UGT isoform. In the longer term, it is hoped that fully defining the "chemical space" recognized by each of the key hepatic UGTs will lead to in silico metabolism screening approaches. The proposed Phase II studies will generate the molecular tools needed to address these needs. The key hepatic UGT isoforms will be expressed, purified and incorporated into HTS assays that can be used to rapidly screen large numbers of diverse chemicals for binding and metabolism by isolated UGT isoforms. These novel molecular assays will fulfill the immediate need for improved preclinical drug glucuronidation assessment, and will accelerate efforts to delineate the key determinants of substrate binding and catalysis for the hepatic UGTs, thereby enabling faster and more cost-effective drug development.