アルデヒドオキシダーゼの阻害機構に関する新規知見～新たな薬物間相互作用の可能性～

2025-10-08

2025-10-07 北海道大学

北海道大学薬学研究院の研究チームは、抗精神病薬クエチアピンとその代謝物が、肝代謝酵素アルデヒドオキシダーゼ(AOX)を阻害することを発見した。AOXは多様な医薬品の代謝に関与するが、その薬物間相互作用は十分に理解されていなかった。研究により、クエチアピンはAOXの還元反応を競合的に阻害し、睡眠薬フルニトラゼパムの代謝を妨げることが判明。酸化反応では非競合的阻害を示すことから、還元部位への結合が示唆された。この成果は、AOXを介した新たな薬物間相互作用のリスク解明と、薬物動態研究の精緻化に貢献する。

アルデヒドオキシダーゼに対するクエチアピンの阻害様式の模式図

<関連情報>

クエチアピンはアルデヒドオキシダーゼによる還元反応に対し競合的阻害効果を示す Quetiapine Competitively Inhibits Aldehyde Oxidase-Mediated Reduction

Hinata Ueda ∙ Shuho Asano ∙ Katsuya Narumi ∙ Ryoichi Aoyagi ∙ Keisuke Okamoto ∙ Masaki Kobayashi
Drug Metabolism and Disposition Published:September 24, 2025
DOI:https://doi.org/10.1016/j.dmd.2025.100169

Abstract

Aldehyde oxidase (AOX) oxidizes nitrogen-containing heterocyclic drugs and reduces electron-deficient nitroaromatic drugs. The aim of this study was to elucidate the mode of inhibition of benzothiazepines such as quetiapine and clozapine, which are known inhibitors of AOX, to predict drug–drug interactions between AOX substrates and inhibitors. Quetiapine and its metabolites inhibited the oxidation and reduction activities of AOX (inhibitory effects: quetiapine ≈ norquetiapine > quetiapine sulfoxide > quetiapine carboxylic acid). The inhibition mode of quetiapine was noncompetitive for phthalazine oxidation (K_i: 5.72 ± 0.88 μM), and competitive for flunitrazepam reduction (K_i: 5.71 ± 0.34 μM). Though a mixed inhibition mode was indicated for the reduction of AOX by clozapine (K_i: 30.91 ± 4.02 μM), the affinity for the enzyme-substrate complex was estimated to be lower than its affinity for the substrate-free enzyme. Based on these results, we expected that benzothiazepines would inhibit activity by becoming trapped in the pocket of AOX, where the electron donor resides. Quetiapine and its metabolites did not inhibit xanthine oxidase (XO) activity, and it is assumed that there are significant structural differences in the sites where the reduction reactions of AOX and XO occur. This is the first study to identify drugs that competitively inhibit the AOX-mediated reduction reactions. The affinities of the inhibitors, especially quetiapine, were higher than those of flunitrazepam used in this study. When evaluating the combined effects of competitive inhibitors on substrate drugs, attention should be paid to the concentrations of both the substrate and the inhibitor.