Ueda Hinata, Narumi Katsuya, Furugen Ayako, Okamoto Keisuke, Saito Yoshitaka, Kobayashi Masaki
Laboratory of Clinical Pharmaceutics and Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-ku, Sapporo 060-0812, Japan.
Education Research Center for Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-ku, Sapporo 060-0812, Japan.
Biol Pharm Bull. 2025;48(5):713-720. doi: 10.1248/bpb.b25-00083.
Thiopurines, such as 6-mercaptopurine (6-MP) and azathioprine, are converted to the inactive metabolites 6-thioxanthin (6-TX) and 6-thiouric acid (6-TUA). Molybdenum-containing oxidoreductases, aldehyde oxidase (AOX) and xanthine oxidase (XO), are involved in the oxidation of 6-MP to 6-TX; XO inhibitors affect the therapeutic efficacy of thiopurines and the incidence of adverse effects, such as liver and blood disorders. However, the role of AOX in the pharmacokinetics of 6-MP remains unclear. To clarify the clinical importance of AOX-mediated drug-drug interactions, we evaluated whether drugs that inhibit AOX affect 6-MP metabolism. The metabolism of 6-MP to 6-TX was strongly inhibited by AOX inhibitors (amitriptyline, chlorpromazine, clomipramine, clozapine, hydralazine, quetiapine, and raloxifene) in a reaction mixture containing human liver cytosol. The inhibition of 6-TX production rate by each AOX inhibitor was 60-70% at high concentrations, although the XO inhibitor febuxostat showed an inhibition rate of 10-30%. Furthermore, the combination of febuxostat and each AOX inhibitor showed greater inhibition than when each compound was added alone. The AOX inhibitor did not alter 6-MP oxidation by recombinant XO. These results suggest that AOX inhibition may affect the pharmacokinetics of thiopurines. However, because of the lower activity of AOX in rats than that in humans, the contribution of AOX could not be assessed using in vivo experiments. Further studies are needed to evaluate the contribution of AOX to the therapeutic and adverse effects of thiopurines, both in clinical studies and in animal models of liver humanization.
硫嘌呤类药物，如6-巯基嘌呤（6-MP）和硫唑嘌呤，会转化为无活性的代谢产物6-硫代黄嘌呤（6-TX）和6-硫尿酸（6-TUA）。含钼的氧化还原酶，醛氧化酶（AOX）和黄嘌呤氧化酶（XO），参与将6-MP氧化为6-TX的过程；XO抑制剂会影响硫嘌呤类药物的治疗效果以及不良反应的发生率，如肝脏和血液疾病。然而，AOX在6-MP药代动力学中的作用仍不清楚。为了阐明AOX介导的药物相互作用的临床重要性，我们评估了抑制AOX的药物是否会影响6-MP的代谢。在含有人类肝脏胞质溶胶的反应混合物中，AOX抑制剂（阿米替林、氯丙嗪、氯米帕明、氯氮平、肼屈嗪、喹硫平和雷洛昔芬）强烈抑制了6-MP向6-TX的代谢。在高浓度下，每种AOX抑制剂对6-TX生成率的抑制率为60-70%，尽管XO抑制剂非布索坦的抑制率为10-30%。此外，非布索坦与每种AOX抑制剂联合使用时的抑制作用比单独添加每种化合物时更强。AOX抑制剂不会改变重组XO对6-MP的氧化作用。这些结果表明，抑制AOX可能会影响硫嘌呤类药物的药代动力学。然而，由于大鼠体内AOX的活性低于人类，因此无法通过体内实验评估AOX的作用。需要进一步的研究，在临床研究和肝脏人源化动物模型中，评估AOX对硫嘌呤类药物治疗效果和不良反应的作用。
