Aldehyde oxidase and its role as a drug metabolizing enzyme

Aldehyde oxidase (AO) is a cytosolic enzyme that belongs to the family of structurally related molybdoflavoproteins like xanthine oxidase (XO). The enzyme is characterized by broad substrate specificity and marked species differences. It catalyzes the oxidation of aromatic and aliphatic aldehydes and various heteroaromatic rings as well as reduction of several functional groups. The references to AO and its role in metabolism date back to the 1950s, but the importance of this enzyme in the metabolism of drugs has emerged in the past fifteen years. Several reviews on the role of AO in drug metabolism have been published in the past decade indicative of the growing interest in the enzyme and its influence in drug metabolism. Here, we present a comprehensive monograph of AO as a drug metabolizing enzyme with emphasis on marketed drugs as well as other xenobiotics, as substrates and inhibitors. Although the number of drugs that are primarily metabolized by AO are few, the impact of AO on drug development has been extensive. We also discuss the effect of AO on the systemic exposure and clearance these clinical candidates. The review provides a comprehensive analysis of drug discovery compounds involving AO with the focus on developmental candidates that were reported in the past five years with regards to pharmacokinetics and toxicity. While there is only one known report of AO-mediated clinically relevant drug-drug interaction (DDI), a detailed description of inhibitors and inducers of AO known to date has been presented here and the potential risks associated with DDI. The increasing recognition of the importance of AO has led to significant progress in predicting the site of AO-mediated metabolism using computational methods. Additionally, marked species difference in expression of AO makes it is difficult to predict human clearance with high confidence. The progress made towards developing in vivo, in vitro and in silico approaches for predicting AO metabolism and estimating human clearance of compounds that are metabolized by AO have also been discussed.