非布司他及其主要的酰基葡萄糖醛酸代谢物是有机阴离子转运体的有效抑制剂3:与利伐沙班药物相互作用的意义

IF 1.7 4区 医学 Q3 PHARMACOLOGY & PHARMACY
Lloyd Wei Tat Tang, Tino Woon Huai Cheong, Eric Chun Yong Chan
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引用次数: 1

摘要

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)介导的依那普利的摄取。本实验研究了非布司他和非布司他AG对转染人胚胎肾293细胞中OAT3的抑制作用。我们的转运体抑制实验证实了非布司他和非布司他AG对oat3介导的雌酮-3-硫酸酯运输的非竞争性和竞争性抑制作用,其相应的表观Ki值分别为0.55和6.11 μM。在考虑探针底物依赖性和蛋白质结合效应后,使用直接因子Xa抗凝剂利伐沙班进行的机制静态建模估计,基于OAT3相互作用,与非布司他合用时,利伐沙班全身暴露增加1.47倍,这反过来使房颤患者的出血风险从基线增加1.51倍。综上所述,我们的研究结果表明,非布司他与利伐沙班合用可能最终导致具有临床意义的药物相互作用,并由于其对OAT3的抑制而导致出血风险增加。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Febuxostat and its major acyl glucuronide metabolite are potent inhibitors of organic anion transporter 3: Implications for drug-drug interactions with rivaroxaban

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 Ki 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.

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来源期刊
CiteScore
3.60
自引率
0.00%
发文量
35
审稿时长
6-12 weeks
期刊介绍: Biopharmaceutics & Drug Dispositionpublishes original review articles, short communications, and reports in biopharmaceutics, drug disposition, pharmacokinetics and pharmacodynamics, especially those that have a direct relation to the drug discovery/development and the therapeutic use of drugs. These includes: - animal and human pharmacological studies that focus on therapeutic response. pharmacodynamics, and toxicity related to plasma and tissue concentrations of drugs and their metabolites, - in vitro and in vivo drug absorption, distribution, metabolism, transport, and excretion studies that facilitate investigations related to the use of drugs in man - studies on membrane transport and enzymes, including their regulation and the impact of pharmacogenomics on drug absorption and disposition, - simulation and modeling in drug discovery and development - theoretical treatises - includes themed issues and reviews and exclude manuscripts on - bioavailability studies reporting only on simple PK parameters such as Cmax, tmax and t1/2 without mechanistic interpretation - analytical methods
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