Development, optimization and implementation of a centralized metabolic soft spot assay
April 2017
Abstract
Aim
High clearance is a commonly encountered issue in drug discovery. Here we present a centralized metabolic soft spot identification assay with adequate capacity and turnaround time to support the metabolic optimization needs of an entire discovery organization.
Methodology
An integrated quan/qual approach utilizing both an orthogonal sample-pooling methodology and software-assisted structure elucidation was developed to enable the assay. Major metabolic soft spots in liver microsomes (rodent and human) were generated in a batch mode, along with kinetics of parent disappearance and metabolite formation, typically within 1 week of incubation.
Results & conclusion
A centralized metabolic soft spot identification assay has been developed and has successfully impacted discovery project teams in mitigating instability and establishing potential structure-metabolism relationships.
Keywords
Dual-concentration incubation; metabolic soft spot; metabolic stability; orthogonal sample pooling; software assisted data processing.