Novel in Vitro Method Reveals Drugs That Inhibit Organic Solute Transporter Alpha/Beta (OSTα/β).,Molecular Pharmaceutics

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Novel in Vitro Method Reveals Drugs That Inhibit Organic Solute Transporter Alpha/Beta (OSTα/β).
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2018-12-14 , DOI: 10.1021/acs.molpharmaceut.8b00966
Melina M Malinen ₁ , Antti Kauttonen _{1,

2} , James J Beaudoin ₁ , Noora Sjöstedt ₁ , Paavo Honkakoski ₂ , Kim L R Brouwer ₁

Affiliation

Drug interactions with the organic solute transporter alpha/beta (OSTα/β) are understudied even though OSTα/β is an important transporter that is expressed in multiple human tissues including the intestine, kidneys, and liver. In this study, an in vitro method to identify novel OSTα/β inhibitors was first developed using OSTα/β-overexpressing Flp-In 293 cells. Incubation conditions were optimized using previously reported OSTα/β inhibitors. A method including a 10 min preincubation step with the test compound was used to screen for OSTα/β inhibition by 77 structurally diverse compounds and fixed-dose combinations. Seven compounds and one fixed-dose combination (100 μM final concentration) inhibited OSTα/β-mediated dehydroepiandrosterone sulfate (DHEAS) uptake by >25%. Concentration-dependent OSTα/β inhibition was evaluated for all putative inhibitors (atorvastatin, ethinylestradiol, fidaxomicin, glycochenodeoxycholate, norgestimate, troglitazone, and troglitazone sulfate). Ethinylestradiol, fidaxomicin, and troglitazone sulfate yielded a clear concentration-inhibition response with IC50 values <200 μM. Among all tested compounds, there was no clear association between physicochemical properties, the severity of hepatotoxicity, and the degree of OSTα/β inhibition. This study utilized a novel in vitro method to identify OSTα/β inhibitors and, for the first time, provided IC50 values for OSTα/β inhibition. These data provide evidence that several drugs, some of which are associated with cholestatic drug-induced liver injury, may impair the function of the OSTα/β transporter.

中文翻译：

新颖的体外方法揭示了抑制有机溶质转运蛋白 Alpha/Beta (OSTα/β) 的药物。

尽管 OSTα/β 是一种重要的转运蛋白，在多种人体组织（包括肠、肾和肝脏）中表达，但药物与有机溶质转运蛋白 α/β (OSTα/β) 的相互作用尚未得到充分研究。在本研究中，首先使用过表达 OSTα/β 的 Flp-In 293 细胞开发了一种鉴定新型 OSTα/β 抑制剂的体外方法。使用先前报道的 OSTα/β 抑制剂优化孵育条件。使用包括与测试化合物预孵育 10 分钟步骤的方法来筛选 77 种结构不同的化合物和固定剂量组合对 OSTα/β 的抑制作用。七种化合物和一种固定剂量组合（100 μM 最终浓度）可抑制 OSTα/β 介导的硫酸脱氢表雄酮 (DHEAS) 摄取>25%。对所有推定抑制剂（阿托伐他汀、炔雌醇、非达霉素、甘鹅去氧胆酸盐、诺孕酯、曲格列酮和硫酸曲格列酮）的浓度依赖性 OSTα/β 抑制进行了评估。炔雌醇、非达霉素和硫酸曲格列酮产生明显的浓度抑制反应，IC50 值<200 μM。在所有测试的化合物中，理化性质、肝毒性的严重程度和 OSTα/β 抑制程度之间没有明确的关联。这项研究利用一种新颖的体外方法来鉴定 OSTα/β 抑制剂，并首次提供了 OSTα/β 抑制的 IC50 值。这些数据提供证据表明，多种药物（其中一些与胆汁淤积药物引起的肝损伤有关）可能会损害 OSTα/β 转运蛋白的功能。

更新日期：2018-11-27

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