Quetiapine competitively inhibits aldehyde oxidase-mediated reduction

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). Although 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. On the basis of 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 activity, and it is assumed that there are significant structural differences in the sites where the reduction reactions of AOX and xanthine oxidase occur. To our knowledge, 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. SIGNIFICANCE STATEMENT: Quetiapine inhibited the oxidative reaction of aldehyde oxidase noncompetitively and the reductive reaction competitively, suggesting that benzothiazepines tend to bind to the reductive pocket of aldehyde oxidase.