Identification of Febuxostat as a New Strong ABCG2 Inhibitor: Potential Applications and Risks in Clinical Situations.
Identification of Febuxostat as a New Strong ABCG2 Inhibitor: Potential Applications and Risks in Clinical Situations.
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非布索坦作为新型强 ABCG2 抑制剂的鉴定：临床情况下的潜在应用和风险。
DOI：
10.3389/fphar.2016.00518
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发表时间：
2016
影响因子：
5.6
通讯作者：
Suzuki H
中科院分区：
文献类型：
--
作者：
Miyata H;Takada T;Toyoda Y;Matsuo H;Ichida K;Suzuki H
ATP结合盒转运体G2（ABCG 2）是一种质膜蛋白，可调节多种药物的药代动力学和人体血清尿酸（SUA）水平。尽管这种转运蛋白具有药理学和生理学重要性，但目前还没有临床可用的药物调节ABCG 2功能。因此，为了鉴定这些药物，我们研究了影响SUA水平的药物对ABCG 2功能的影响。这一策略基于这样的假设，即SUA水平的变化可能是由于与ABCG 2的相互作用引起的，因为ABCG 2是生理上重要的尿酸盐转运蛋白。体外筛选的结果表明，25种药物中有10种强烈抑制ABCG 2的尿酸盐转运活性。此外，基于其在临床浓度下的强效抑制作用，非布司他被认为是所有潜在ABCG 2抑制剂中最有希望的候选药物;非布司他的半数最大抑制浓度低于报告的最大血浆未结合浓度。事实上，我们的体内研究表明，口服非布司他抑制肠道Abcg 2，从而增加野生型小鼠对ABCG 2底物柳氮磺胺吡啶的肠道吸收，但在Abcg 2敲除小鼠中则不然。这些结果表明，非布司他可能在临床剂量下抑制人ABCG 2。此外，本研究的结果导致提出了非布司他用于增强ABCG 2底物药物的生物利用度的新应用，称为非布司他增强疗法，并且还暗示了非布司他和ABCG 2底物药物之间可能发生的药物-药物相互作用的潜在不良反应风险。
ATP-binding cassette transporter G2 (ABCG2) is a plasma membrane protein that regulates the pharmacokinetics of a variety of drugs and serum uric acid (SUA) levels in humans. Despite the pharmacological and physiological importance of this transporter, there is no clinically available drug that modulates ABCG2 function. Therefore, to identify such drugs, we investigated the effect of drugs that affect SUA levels on ABCG2 function. This strategy was based on the hypothesis that the changes of SUA levels might caused by interaction with ABCG2 since it is a physiologically important urate transporter. The results of the in vitro screening showed that 10 of 25 drugs investigated strongly inhibited the urate transport activity of ABCG2. Moreover, febuxostat was revealed to be the most promising candidate of all the potential ABCG2 inhibitors based on its potent inhibition at clinical concentrations; the half-maximal inhibitory concentration of febuxostat was lower than its maximum plasma unbound concentrations reported. Indeed, our in vivo study demonstrated that orally administered febuxostat inhibited the intestinal Abcg2 and, thereby, increased the intestinal absorption of an ABCG2 substrate sulfasalazine in wild-type mice, but not in Abcg2 knockout mice. These results suggest that febuxostat might inhibit human ABCG2 at a clinical dose. Furthermore, the results of this study lead to a proposed new application of febuxostat for enhancing the bioavailability of ABCG2 substrate drugs, named febuxostat-boosted therapy, and also imply the potential risk of adverse effects by drug-drug interactions that could occur between febuxostat and ABCG2 substrate drugs.