Strategies for a comprehensive understanding of metabolism by aldehyde oxidase

Aldehyde oxidase (AO) is a drug-metabolizing molybdo-flavoenzyme with profound species differences in expression and activity toward various substrates. The contribution of this enzyme to the metabolism and clearance of heterocyclic-containing xenobiotics appears to have increased in recent years, but has not always been identified prior to clinical studies. As a result, drug candidates have been negatively impacted in development.

This review provides the most recent in vitro and in vivo strategies for the drug metabolism-pharmacokinetic (DMPK) scientist. The review details approaches for confirmation of AO as an operable metabolic pathway, estimating clearance and fraction of total metabolism, and identification of an appropriate surrogate species for human AO activity for evaluating safety of clinically relevant metabolites.

As the role of AO in metabolism of new drug molecules continues to emerge, it is critical that DMPK scientists have the most updated methodologies to enable formulation of a thorough experimental plan to understand the potential implications of this metabolic pathway. Whether it is higher-than-expected clearance, contributing to an unfavorable half-life, or the formation of an AO-derived disproportionate human metabolite (DHM), such a plan would serve to minimize complications or attrition of drug candidates due to unforeseen issues in the clinic.