An increasing number of drugs are metabolized by aldehyde oxidase (AOX), but AOX-mediated drug interactions are seldom reported due to the lack of appropriate inhibitors and inducers. A recent study reported that nimesulide (NIM) could increase the liver injury risk of methotrexate. The latter was mainly metabolized by AOX to form hepatotoxic 7-hydroxymethotrexate (7-OH MTX). Thus, we speculated that NIM could induce AOX. In this study, we investigated the potential induction of AOX activity by NIM using methotrexate as the probe substrate. Treatment of primary human and rat hepatocytes with NIM (20 μM) for 24 h caused a 2.0- and 3.1-fold, respectively, increase in 7-OH MTX formation. Oral administration of NIM (100 mg·kg⁻¹·d⁻¹, for 5 days) to rats significantly increased the systematic exposure (6.5-fold), liver distribution (2.5-fold), and excretion (5.2-fold for urinary excretion and 2.1-fold for fecal excretion) of 7-OH MTX. The 7-OH MTX formation in liver cytosol from rats pretreated with 20, 50, and 100 mg·kg⁻¹·d⁻¹ NIM for 5 days increased by 1.9-, 3.2-, and 3.7-fold, respectively, compared with that of rats pretreated with the vehicle. We revealed that the elevation of AOX activity was accompanied by an increase in AOX1 protein levels but not the corresponding mRNA levels. Collectively, our results demonstrate for the first time that NIM can increase the AOX activity of humans and rats, and may raise concerns regarding the risk of drug interactions between NIM and AOX substrates in clinical practice.

越来越多的药物通过醛氧化酶 (AOX) 代谢，但由于缺乏适当的抑制剂和诱导剂，很少报道 AOX 介导的药物相互作用。最近的一项研究报告称，尼美舒利 (NIM) 可能会增加甲氨蝶呤的肝损伤风险。后者主要由 AOX 代谢形成具有肝毒性的 7-羟基甲氨蝶呤 (7-OH MTX)。因此，我们推测 NIM 可以诱导 AOX。在这项研究中，我们使用甲氨蝶呤作为探针底物研究了 NIM 对 AOX 活性的潜在诱导作用。用 NIM (20 μM) 处理原代人和大鼠肝细胞 24 小时分别导致 7-OH MTX 形成增加 2.0 倍和 3.1 倍。口服 NIM (100 mg·kg ^-1 ·d ^-1, 5 天) 对大鼠的 7-OH MTX 系统暴露量 (6.5 倍)、肝脏分布 (2.5 倍) 和排泄 (尿排泄 5.2 倍，粪便排泄 2.1 倍) 显着增加。^{与对照组相比，经 20、50 和 100 mg·kg -1} ·d ^-1 NIM预处理 5 天的大鼠肝细胞质中 7-OH MTX 的形成分别增加了 1.9 倍、3.2 倍和 3.7 倍。用载体预处理的大鼠。我们发现 AOX 活性的升高伴随着 AOX1 蛋白水平的增加，但不是相应的 mRNA 水平。总的来说，我们的研究结果首次证明 NIM 可以增加人类和大鼠的 AOX 活性，并可能引起人们对临床实践中 NIM 和 AOX 底物之间药物相互作用风险的担忧。