title: Significance of aldehyde oxidase during drug development: Effects on drug metabolism, pharmacokinetics, toxicity, and efficacy.
abstract: Aldehyde oxidase contributes to drug metabolism and pharmacokinetics (PK), and a few clinical studies were discontinued because of aldehyde oxidase metabolism. Its AOX1, AOX3, AOX3L1, and AOX4 isoforms are expressed in mammals, and species differences in expression profiles reflect differences in drug metabolism and PK between animals and humans. Individual differences in aldehyde oxidase activity also influence drug metabolism in humans. Moreover, the reduced solubility of the aldehyde oxidase metabolites may induce drug toxicity. Because various drugs inhibit aldehyde oxidase, assessments of ensuing drug-drug interactions (DDI) are critical for drug optimization. Although drug metabolism, PK, safety, and DDI are important, drugs such as famciclovir and O6-benzylguanine that affect aldehyde oxidase activity in humans have been reported. Recently, various in vitro approaches have been developed to predict PK in humans. However, in vitro studies on aldehyde oxidase may be hampered because of its instability. In contrast, in vivo studies on chimeric mice with humanized livers have also been focused on to predict aldehyde oxidase-mediated metabolism. Additionally, the ratios of N1-methylnicotinamide to metabolites in urinary excretions may represent useful biomarkers of aldehyde oxidase activity in humans. Thus, assessing the contributions of aldehyde oxidase to drug metabolism in humans is necessary.
authors.affiliation: Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan. Electronic address: sanoh@hiroshima-u.ac.jp.
authors.forename: Seigo
authors.initials: S
authors.lastname: Sanoh
authors.affiliation: Faculty of Pharmaceutical Science, Hiroshima International University, Hiroshma, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Tayama
authors.affiliation: Faculty of Pharmaceutical Science, Hiroshima International University, Hiroshma, Japan.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Sugihara
authors.affiliation: Nihon Pharmaceutical University, Saitama, Japan.
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Kitamura
authors.affiliation: Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Ohta
mesh_terms: D042931:Aldehyde Oxidase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001711:Biotransformation; D055808:Drug Discovery / Q000379:methods*; D004347:Drug Interactions; D064420:Drug-Related Side Effects and Adverse Reactions / Q000201:enzymology* / Q000209:etiology; D015507:Drugs, Investigational / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D015394:Molecular Structure; D011237:Predictive Value of Tests; D013045:Species Specificity; D013379:Substrate Specificity
chemical_list: D015507:Drugs, Investigational; D042931:Aldehyde Oxidase
keywords: Aldehyde oxidase; Chimeric mice with humanized livers; Efficacy; Hepatocytes; Individual differences; Metabolism; Pharmacokinetics; Species differences; Toxicity