美国诺华生物医学研究所Laszlo Urban和加州大学Brian K. Shoichet研究组合作取得新进展。他们发现了药物非活性成分对生物靶标的活性。相关论文于2020年7月23日发表在《科学》杂志上。

他们计算了批准的赋形剂与分子靶标结合的可能性。体外测试显示25种赋形剂活性，范围从低纳摩尔浓度到高微摩尔浓度。通过针对临床安全靶标进行测试，确定了另外109个赋形剂活性。在细胞模型中，五种赋形剂具有可预测的系统水平毒性印记。

研究中，某些人群接触7种赋形剂，其中2种可能达到体外靶标水平，包括硫柳汞及其主要代谢产物的脑和肠接触，其多巴胺D3受体解离常数Kd值分别为320和210 nM。尽管大多数赋形剂应具有惰性，但许多批准的赋形剂可能直接调节生理相关靶标。

据悉，赋形剂被认为是“非活性成分”，是配制药物的主要成分，并在其药代动力学中发挥关键作用。尽管它们无处不在，但尚未系统地研究它们是否在任何靶标上都活跃。

附：英文原文

Title: The activities of drug inactive ingredients on biological targets

Author: Joshua Pottel, Duncan Armstrong, Ling Zou, Alexander Fekete, Xi-Ping Huang, Hayarpi Torosyan, Dallas Bednarczyk, Steven Whitebread, Barun Bhhatarai, Guiqing Liang, Hong Jin, S. Nassir Ghaemi, Samuel Slocum, Katalin V. Lukacs, John J. Irwin, Ellen L. Berg, Kathleen M. Giacomini, Bryan L. Roth, Brian K. Shoichet, Laszlo Urban

Issue&Volume: 2020/07/24

Abstract: Excipients, considered “inactive ingredients,” are a major component of formulated drugs and play key roles in their pharmacokinetics. Despite their pervasiveness, whether they are active on any targets has not been systematically explored. We computed the likelihood that approved excipients would bind to molecular targets. Testing in vitro revealed 25 excipient activities, ranging from low-nanomolar to high-micromolar concentration. Another 109 activities were identified by testing against clinical safety targets. In cellular models, five excipients had fingerprints predictive of system-level toxicity. Exposures of seven excipients were investigated, and in certain populations, two of these may reach levels of in vitro target potency, including brain and gut exposure of thimerosal and its major metabolite, which had dopamine D3 receptor dissociation constant Kd values of 320 and 210 nM, respectively. Although most excipients deserve their status as inert, many approved excipients may directly modulate physiologically relevant targets.

DOI: 10.1126/science.aaz9906

Source: https://science.sciencemag.org/content/369/6502/403