Aldehyde Oxidase: Why In Vitro Absolute Activity Doesn’t Matter
Presented by: Brian Ogilvie and Faraz Kazmi
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 vivoHuman clearance from in vitro clearance data, which are typically conducted withHuman 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 allHuman 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.
Key concepts discussed in this webinar include:
- Factors that may contribute to the lot-to-lot availability of AO activity
- Utility of the yardstick approach for categorizing in vivo AO clearance of candidate drugs
- Evidence that nearly any lot ofHuman liver S9 or cytosol can be used for this approach