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XenoTech Webinar: Aldehyde Oxidase - Why In Vitro Absolute Activity Doesn't Matter

Sekisui XenoTech

Biotransformation by aldehyde oxidase (AO) is an important clearance mechanism for many drugs and drug candidates, with increasing importance in certain chemical spaces, and in some cases, such as zaleplon, AO metabolism leads to rapid in vivo clearance. Several publications have demonstrated a consistent under-prediction of in vivo human clearance from in vitro clearance data, which are typically conducted with human liver subcellular fractions, such as S9 or cytosol. Zientek and colleagues (2010) described a rank order, or 'yard-stick' approach, to categorize known AO substrates into low, medium or high clearance categories based on in vitro data. With this approach, drug candidates can be evaluated in vitro in S9 or cytosol and the predicted in vivo clearance can be qualitatively ranked from low- to high-clearance. We will present data to show that because of the necessity to scale AO clearance with a rank-order approach, nearly all human liver S9 and cytosol lots (individual or pooled) can be utilized to predict in vivo AO clearance once threshold values are determined with appropriate probe drugs.

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