Abstract

1. To date, relatively little is known about the interactions of pharmaceutical excipients with hepatic and renal drug uptake transporters. The present study was designed to systematically evaluate the effects of 16 commonly consumed excipients on human organic cation transporter 1 and 2 (hOCT1 and hOCT2), human organic anion transporter 1 and 3 (hOAT1 and hOAT3) and human organic anion transporting polypeptide 1B1 and 1B3 (hOATP1B1 and hOATP1B3).

2. The inhibitory effects and mechanisms of excipients on transporters were investigated using in vitro uptake studies, cell viability assays, concentration-dependent studies, and the Lineweaver–Burk plot method.

3. Triton X-100 is a non-competitive inhibitor for all six transporters. Tween 20 inhibits hOCT2, hOAT1, hOAT3, and hOATP1B3 in a mixed way, whereas it competitively inhibits hOATP1B1. The inhibition of Tween 80 is competitive for hOCT2, non-competitive for hOATP1B1 and hOATP1B3, and mixed for hOAT1 and hOAT3. Concentration-dependent studies identify Triton X-100 as a strong inhibitor of hOCT1 and hOCT2 with IC₅₀ values of 20.1 and 4.54 μg/mL, respectively. Additionally, Triton X-100, Tween 20, and Tween 80 strongly inhibit hOAT3 with IC₅₀ values ≤31.0 μg/mL.

4. The present study is significant in understanding the excipient–drug interactions and provides valuable information for excipient selection in drug development.

摘要

1. 迄今为止，关于药物赋形剂与肝和肾药物摄取转运蛋白之间相互作用的了解还很少。本研究旨在系统评估16种常用辅料对人类有机阳离子转运蛋白1和2（hOCT1和hOCT2），人类有机阴离子转运蛋白1和3（hOAT1和hOAT3）和人类有机阴离子转运多肽1B1和1B3的影响（hOATP1B1和hOATP1B3）。

2. 使用体外吸收研究，细胞活力测定，浓度依赖性研究和Lineweaver-Burk图法研究了赋形剂对转运蛋白的抑制作用和机理。

3. Triton X-100是所有六个转运蛋白的非竞争性抑制剂。Tween 20以混合方式抑制hOCT2，hOAT1，hOAT3和hOATP1B3，而竞争性抑制hOATP1B1。吐温80的抑制作用与hOCT2竞争，对hOATP1B1和hOATP1B3不竞争，并且对hOAT1和hOAT3混合。浓度依赖性研究确定Triton X-100是hOCT1和hOCT2的强抑制剂，IC ₅₀值分别为20.1和4.54μg / mL。此外，Triton X-100，Tween 20和Tween 80可以抑制hOAT3，IC ₅₀值≤31.0μg/ mL。

4. 本研究对理解赋形剂与药物的相互作用具有重要意义，并为药物开发中的赋形剂选择提供了有价值的信息。