Richardson_2016_Drug.Metab.Lett_10_83

Reference

Title : Efficiency in Drug Discovery: Liver S9 Fraction Assay As a Screen for Metabolic Stability - Richardson_2016_Drug.Metab.Lett_10_83
Author(s) : Richardson SJ , Bai A , Kulkarni AA , Moghaddam MF
Ref : Drug Metab Lett , 10 :83 , 2016
Abstract :

BACKGROUND: A rapid and comprehensive metabolic stability screen at the top of a drug discovery flow chart serves as an effective gate in eliminating low value compounds. This imparts a significant level of efficiency and saves valuable resources. While microsomes are amenable to high throughput automation and are cost effective, their enzymatic make-up is limited to that which is contained in endoplasmic reticulum, thereby informing only on Phase I metabolism. Lack of Phase II metabolism data can become a potential liability later in the process, adversely affecting discovery projects' timelines and budget. Hepatocytes offer a full complement of metabolic enzymes and retain their cellular compartments, better representing liver metabolic function. However, hepatocyte screens are relatively expensive, labor intensive, and not easily automatable. Liver S9 fractions include Phase I and II metabolic enzymes, are relatively inexpensive, easy to use, and amenable to automation, making them a more appropriate screening system. We compare the data from the three systems and present the results. RESULTS: Liver S9 and hepatocyte stability assays binned into the same category 70-84% of the time. Microsome and hepatocyte data were in agreement 73-82% of the time. The true rate for stability versus plasma clearance was 45% for hepatocytes and 43% for S9. CONCLUSION: In our opinion, replacing liver microsome and hepatocyte assays with S9 assay for high throughput metabolic screening purposes provides the combined benefit of comprehensive and high quality data at a reasonable expense for drug discovery programs.

PubMedSearch : Richardson_2016_Drug.Metab.Lett_10_83
PubMedID: 26902079

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Citations formats

Richardson SJ, Bai A, Kulkarni AA, Moghaddam MF (2016)
Efficiency in Drug Discovery: Liver S9 Fraction Assay As a Screen for Metabolic Stability
Drug Metab Lett 10 :83

Richardson SJ, Bai A, Kulkarni AA, Moghaddam MF (2016)
Drug Metab Lett 10 :83