Abstract：
Recently, anthelmintics have showcased versatile therapeutic potential in addressing various diseases, positioning them as promising candidates for drug repurposing. However, challenges such as low bioavailability and a lack of a solid pharmacokinetic basis impede successful repurposing. To overcome these flaws, we aimed to investigate the key pharmacokinetic factors of anthelmintics mainly focusing on the absorption, distribution, and metabolism profiles by employing niclosamide (NIC) as a model drug. The intestinal permeability of NIC is significantly influenced by solubility and doesn\'t function as a substrate for efflux transporters. It showed high plasma protein binding. Also, the metabolism study indicated that NIC would have low metabolic stability by extensively undergoing the intestinal glucuronidation. Additionally, we investigated the CYP-mediated drug-drug interaction potential of NIC in both direct and time-dependent ways. NIC showed strong inhibitory effects on CYP1A2 and CYP2C8 and is not likely to become a time-dependent inhibitor. Our findings could contribute to the identification of essential factors in the pharmacokinetics of anthelmintics, potentially facilitating their repositioning.
摘要：
最近,驱虫药在解决各种疾病方面展示了多种治疗潜力，将它们定位为有希望的药物再利用候选人。然而,低生物利用度和缺乏坚实的药代动力学基础等挑战阻碍了成功的再利用。为了克服这些缺陷，我们旨在研究驱虫药的关键药代动力学因素，主要集中在吸收，分布，和代谢概况通过使用氯硝柳胺（NIC）作为模型药物。NIC的肠通透性受溶解度的影响很大，不能作为外排转运蛋白的底物。它显示了高的血浆蛋白结合。此外，代谢研究表明，通过广泛进行肠道葡萄糖醛酸化，NIC将具有较低的代谢稳定性。此外,我们以直接和时间依赖性方式研究了CYP介导的NIC药物-药物相互作用潜力.NIC对CYP1A2和CYP2C8显示出强烈的抑制作用，并且不太可能成为时间依赖性抑制剂。我们的发现可能有助于确定驱虫药的药代动力学中的基本因素，有可能促进他们的重新定位。
