Febuxostat is a second-line xanthine oxidase inhibitor that undergoes extensive hepatic metabolism to yield its major acyl-β-D-glucuronide metabolite (febuxostat AG). It was recently reported that febuxostat inhibited organic anion transporter 3 (OAT3)-mediated uptake of enalaprilat. Here, we investigated the inhibition of febuxostat and febuxostat AG on OAT3 in transfected human embryonic kidney 293 cells. Our transporter inhibition assays confirmed the potent noncompetitive and competitive inhibition of OAT3-mediated estrone-3-sulfate transport by febuxostat and febuxostat AG with corresponding apparent K_i values of 0.55 and 6.11 μM respectively. After accounting for probe substrate-dependency and protein binding effects, mechanistic static modelling with the direct factor Xa anticoagulant rivaroxaban estimated a 1.47-fold increase in its systemic exposure when co-administered with febuxostat based on OAT3 interaction which in turn exacerbates the bleeding risk from baseline for patients with atrial fibrillation by 1.51-fold. Taken together, our results suggested that the concomitant usage of febuxostat with rivaroxaban may potentially culminate in a clinically-significant drug-drug interaction and result in an increased risk of bleeding as a result of its OAT3 inhibition.

中文翻译：

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非布司他及其主要的酰基葡糖苷酸代谢物是有机阴离子转运蛋白 3 的强效抑制剂：与利伐沙班的药物-药物相互作用的意义

非布司他是一种二线黄嘌呤氧化酶抑制剂，经过广泛的肝脏代谢产生其主要的酰基-β -D-葡糖苷酸代谢物（非布司他 AG）。最近有报道称，非布司他抑制有机阴离子转运蛋白 3 (OAT3) 介导的依那普利拉摄取。在这里，我们研究了非布司他和非布司他 AG 对转染的人胚胎肾 293 细胞中 OAT3 的抑制作用。我们的转运蛋白抑制试验证实了非布索坦和非布索坦 AG 对 OAT3 介导的 estrone-3-sulfate 转运具有有效的非竞争性和竞争性抑制作用，并具有相应的表观K _i值分别为 0.55 和 6.11 μM。在考虑了探针底物依赖性和蛋白质结合效应后，使用直接因子 Xa 抗凝剂利伐沙班的机械静态模型估计，当基于 OAT3 相互作用与非布索坦共同给药时，其全身暴露增加 1.47 倍，这反过来又加剧了出血风险心房颤动患者的基线值增加了 1.51 倍。总之，我们的研究结果表明，非布司他与利伐沙班的同时使用可能最终导致临床上显着的药物-药物相互作用，并由于其 OAT3 抑制而导致出血风险增加。