Xi Ruqi, Abdulla Rahima, Zhao Jiangyu, Aisa Haji Akber, Liu Yongqiang
State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi 830011, China.
University of Chinese Academy of Sciences, No. 19(A) Yuquan Road, Shijingshan District, Beijing 100049, China.
Pharmaceuticals (Basel). 2023 May 11;16(5):728. doi: 10.3390/ph16050728.
Given the limitations of existing antiviral drugs and vaccines, there is still an urgent need for new anti-influenza drugs. CAM106, a rupestonic acid derivative, was studied for its potent antiviral activity and showed a favorable inhibitory effect on influenza virus replication. However, many gaps exist in preclinical studies of CAM106. This study focused on the pharmacokinetic profile and metabolites of CAM106 in vivo. An efficient and fast bioanalytical method was successfully developed and validated for the quantitation of CAM106 in rat plasma. A mobile phase aqueous solution (A, containing 0.1% formic acid) and acetonitrile (B) worked within 0-3.5 min, with 60% B. The mass spectrum scanning mode was the parallel reaction monitoring (PRM) with a resolution of 17,500. The linear range of the method was 2.13-1063.83 ng/mL. The validated method was applied to a pharmacokinetic study in rats. The matrix effects ranged from 93.99% to 100.08% and the recovery ranged from 86.72% to 92.87%. The intra- and inter-day precisions were less than 10.24% and the relative error (RE) ranged from -8.92% to 7.1%. The oral bioavailability of CAM106 was 1.6%. Thereafter, its metabolites in rats were characterized using high-resolution mass spectrometry. The isomers M7-A, M7-B, M7-C, and M7-D were well separated. As a result, a total of 11 metabolites were identified in the feces, urine, and plasma of rats. The main metabolic pathways of CAM106 were oxidation, reduction, desaturation, and methylation. The assay was reliable and provided useful information for further clinical studies of CAM106.
鉴于现有抗病毒药物和疫苗的局限性，新型抗流感药物的需求仍然迫切。CAM106是一种鲁佩斯托酸衍生物，因其强大的抗病毒活性而被研究，并对流感病毒复制显示出良好的抑制作用。然而，CAM106的临床前研究存在许多空白。本研究聚焦于CAM106在体内的药代动力学特征和代谢产物。成功开发并验证了一种高效快速的生物分析方法，用于定量大鼠血浆中的CAM106。流动相水溶液（A，含0.1%甲酸）和乙腈（B）在0 - 3.5分钟内以60%B的比例运行。质谱扫描模式为平行反应监测（PRM），分辨率为17,500。该方法的线性范围为2.13 - 1063.83 ng/mL。验证后的方法应用于大鼠药代动力学研究。基质效应范围为93.99%至100.08%，回收率范围为86.72%至92.87%。日内和日间精密度均小于10.24%，相对误差（RE）范围为 - 8.92%至7.1%。CAM106口服生物利用度为1.6%。此后，利用高分辨率质谱对其在大鼠体内的代谢产物进行了表征。异构体M7 - A、M7 - B、M7 - C和M7 - D得到了很好的分离。结果，在大鼠粪便、尿液和血浆中总共鉴定出11种代谢产物。CAM106的主要代谢途径为氧化、还原、去饱和化和甲基化。该测定方法可靠，为CAM106的进一步临床研究提供了有用信息。
