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Aldehyde oxidase (AO) has garnered curiosity as a non-CYP metabolizing enzyme in drug development due to unexpected consequences such as toxic metabolite generation and high metabolic clearance resulting in the clinical failure of new drugs. Therefore, poor AO mediated clearance prediction in preclinical nonhuman species remains a significant obstacle in developing novel drugs. Various isoforms of AO, such as  AOX1, AOX3, AOX3L1 , and  AOX4  exist across species, and different AO activity among humans influences the AO mediated drug metabolism. Therefore, carefully considering the unique challenges is essential in developing successful AO substrate drugs. The  in vitro  to  in vivo  extrapolation underpredicts AO mediated drug clearance due to the lack of reliable representative animal models, substrate-specific activity, and the discrepancy between absolute concentration and activity. An  in vitro  tool to extrapolate  in vivo  clearance using a yard-stick approach is provided to address the underprediction of AO mediated drug clearance. This approach uses a range of well-known AO drug substrates as calibrators for qualitative scaling new drugs into low, medium, or high clearance category drugs. So far,  in vivo  investigations on chimeric mice with humanized livers (humanized mice) have predicted AO mediated metabolism to the best extent. This review addresses the critical aspects of the drug discovery stage for AO metabolism studies, challenges faced in drug development, approaches to tackle AO mediated drug clearance’s underprediction, and strategies to decrease the AO metabolism of drugs.

Aldehyde oxidase mediated drug metabolism: an underpredicted obstacle in drug discovery and development