Pharmacotherapeutics Unit, Department of Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia.
International Medical University, No.126, Jalan Jalil Perkasa 19, Bukit Jalil, 57000, Kuala Lumpur, Malaysia.
Naunyn Schmiedebergs Arch Pharmacol. 2021 Jan;394(1):95-105. doi: 10.1007/s00210-020-01966-3. Epub 2020 Aug 25.
SRS27, an andrographolide analogue, had been proven to have therapeutic properties at a dose of 3 mg/kg in both in vitro and in vivo asthma models of our previous study. The present study focuses on the pharmacokinetic and toxicity profile of this compound to provide further evidence for the development of this compound as an anti-asthma agent. A simple pharmacokinetic study was performed in female BALB/c mice to measure blood plasma concentration of the compound at therapeutic dose. At a single dose of 3 mg/kg, SRS27 had a relatively short half-life but was able to achieve a concentration range of 13-19 μM that is related to its in vitro bioactivities. With regard to toxicity profile, SRS27 appears to be safe, as no histopathological changes were observed in the liver, kidneys and ovaries of SRS27-treated female BALB/c mice. In addition, there was no significant change in the mean body weight and organ weight of the animals in the SRS27-treated groups compared with the vehicle-treated control group at the end of the treatment. This fully supports the absence of any significant changes in peripheral blood leukocyte counts of SRS27-treated mice. Rewardingly, this acute toxicity study also revealed that SRS27 has a wide therapeutic window as no toxicity symptoms were detected with a dose up to 60 mg/kg daily when tested for 14 days. These results provide strong justification for further investigation of SRS27 as a potential new anti-asthma agent.
SRS27 是一种穿心莲内酯类似物，在我们之前的研究中，已证明其在体外和体内哮喘模型中，3mg/kg 的剂量具有治疗作用。本研究侧重于该化合物的药代动力学和毒性特征，为将该化合物开发为抗哮喘药物提供进一步的证据。在雌性 BALB/c 小鼠中进行了一项简单的药代动力学研究，以测量治疗剂量下化合物的血浆浓度。在 3mg/kg 的单剂量下，SRS27 的半衰期相对较短，但能够达到与其体外生物活性相关的 13-19μM 的浓度范围。关于毒性特征，SRS27 似乎是安全的，因为在 SRS27 治疗的雌性 BALB/c 小鼠的肝、肾和卵巢中未观察到组织病理学变化。此外，与对照组相比，SRS27 治疗组的动物在治疗结束时的平均体重和器官重量没有明显变化。这完全支持 SRS27 治疗小鼠的外周血白细胞计数没有任何显著变化。令人欣慰的是，这项急性毒性研究还表明，SRS27 具有较宽的治疗窗，因为在 14 天的测试中，当剂量高达 60mg/kg/天时，未检测到毒性症状。这些结果为进一步将 SRS27 作为一种有潜力的新型抗哮喘药物进行研究提供了有力依据。
