China Resources Double-Crane Pharmaceutical Co., Ltd. Beijing 100102,China.
Fengtai Maternal and Child Health Care Hospital, Beijing 100069,China.
Med Chem. 2022;18(1):140-150. doi: 10.2174/1573406416666201120102905.
The broad-spectrum antiparasitic drug nitazoxanide (N) has been repositioned as a broad-spectrum antiviral drug. Nitazoxanide's in vivo antiviral activities are mainly attributed to its metabolite-tizoxanide, the deacetylation product of nitazoxanide. In reference to the pharmacokinetic profile of nitazoxanide, we proposed the hypotheses that the low plasma concentrations and the low system exposure of tizoxanide after dosing with nitazoxanide result from significant first-pass effects in the liver. It was thought that this might be due to the unstable acyloxy bond of nitazoxanide.
Tizoxanide prodrugs, with the more stable formamyl substituent attached to the hydroxyl group rather than the acetyl group of nitazoxanide, were designed with the thought that they might be more stable in plasma. It was anticipated that these prodrugs might be less affected by the first pass effect, which would improve plasma concentrations and system exposure of tizoxanide.
These O-carbamoyl tizoxanide prodrugs were synthesized and evaluated in a mouse model for pharmacokinetic (PK) properties and in an in vitro model for plasma stabilities.
The results indicated that the plasma concentration and the systemic exposure of tizoxanide (T) after oral administration of O-carbamoyl tizoxanide prodrugs were much greater than that produced by the equimolar dosage of nitazoxanide. It was also found that the plasma concentration and the systemic exposure of tizoxanide glucuronide (TG) were much lower than that produced by nitazoxanide.
Further analysis showed that the suitable plasma stability of O-carbamoyl tizoxanide prodrugs is the key factor in maximizing the plasma concentration and the systemic exposure of the active ingredient tizoxanide.
广谱抗寄生虫药物硝唑尼特（N）已被重新定位为广谱抗病毒药物。硝唑尼特的体内抗病毒活性主要归因于其代谢物替硝唑，即硝唑尼特的去乙酰化产物。参考硝唑尼特的药代动力学特征，我们提出了以下假设：硝唑尼特给药后替硝唑的低血浆浓度和低系统暴露归因于肝脏中的显著首过效应。这可能是由于硝唑尼特的酰氧基键不稳定。
替硝唑前药，其稳定的甲酰氨基取代基连接在羟基上而不是硝唑尼特的乙酰基上，设计思路是它们在血浆中可能更稳定。预计这些前药可能受首过效应的影响较小，这将提高替硝唑的血浆浓度和系统暴露。
这些 O-氨基甲酰替硝唑前药已在小鼠模型中进行了药代动力学（PK）特性评估，并在体外血浆稳定性模型中进行了评估。
结果表明，口服 O-氨基甲酰替硝唑前药后替硝唑（T）的血浆浓度和系统暴露明显大于等摩尔剂量的硝唑尼特。还发现替硝唑葡萄糖醛酸（TG）的血浆浓度和系统暴露明显低于硝唑尼特。
进一步分析表明，O-氨基甲酰替硝唑前药的合适血浆稳定性是最大化活性成分替硝唑的血浆浓度和系统暴露的关键因素。
