Development, optimization and implementation of a centralized metabolic soft spot assay. (April 2017)

• Record Type: Journal Article
• Authors: Paiva, Anthony A; Klakouski, Cheryl; Li, Shu; Johnson, Benjamin M; Shu, Yue-Zhong; Josephs, Jonathan; Zvyaga, Tatyana; Zamora, Ismael; Shou, Wilson Z
• Is Part Of: Bioanalysis. Volume 9:Number 7(2017)
• Page Start: 541
• Page End: 552
• Publication Date: 2017-04
• Subjects: dual-concentration incubation -- metabolic soft spot -- metabolic stability -- orthogonal sample pooling -- software assisted data processing; Drugs -- Analysis -- Periodicals; 615.19005
• DOI: 10.4155/bio-2016-0299
• Languages: English
• ISSNs: 1757-6180

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.