Miyata Hiroshi, Takada Tappei, Toyoda Yu, Matsuo Hirotaka, Ichida Kimiyoshi, Suzuki Hiroshi
Department of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo Tokyo, Japan.
Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College Tokorozawa, Japan.
Front Pharmacol. 2016 Dec 27;7:518. doi: 10.3389/fphar.2016.00518. eCollection 2016.
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 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 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 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.
ATP结合盒转运体G2（ABCG2）是一种质膜蛋白，可调节多种药物的药代动力学以及人体血清尿酸（SUA）水平。尽管该转运体在药理学和生理学上具有重要意义，但目前尚无临床上可用于调节ABCG2功能的药物。因此，为了鉴定此类药物，我们研究了影响SUA水平的药物对ABCG2功能的作用。该策略基于这样的假设：由于ABCG2是一种重要的生理性尿酸转运体，SUA水平的变化可能是由与ABCG2的相互作用引起的。筛选结果显示，在研究的25种药物中，有10种强烈抑制ABCG2的尿酸转运活性。此外，基于非布司他在临床浓度下的强效抑制作用，它被证明是所有潜在ABCG2抑制剂中最有前景的候选药物；非布司他的半数最大抑制浓度低于其报道的最大血浆游离浓度。实际上，我们的研究表明，口服非布司他可抑制野生型小鼠肠道中的Abcg2，从而增加ABCG2底物柳氮磺胺吡啶的肠道吸收，但在基因敲除小鼠中则无此作用。这些结果表明，非布司他可能在临床剂量下抑制人类ABCG2。此外，本研究结果提出了非布司他的一种新应用，即增强ABCG2底物药物的生物利用度，称为非布司他增强疗法，同时也暗示了非布司他与ABCG2底物药物之间可能发生药物相互作用而产生不良反应的潜在风险。
