Effective Screening Methods and Use of Quantitative and Qualitative LC/MS/MS to Minimize Aldehyde Oxidase Mediated Metabolism in Discovery Programs

摘要

1. In this program, the substrates of interest had excellent potency and ADME properties in microsomal (rat, dog, human) and human cytosol incubations. However, high Cl_(int) properties were observed in rat cytosol and were corroborated during in-vivo rat PK studies (t_(1/2)=0.5hr). 2. Typically, animal study data are extrapolated and used to predict human PK profiles through allometric scaling, but the models assume that physiological and biochemical variables can be scaled across species as a function of weight. Thus, effective modeling for human PK parameters would not be possible unless the issue of AO-mediated metabolism was resolved in the rat.