Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
Key Laboratory of Acupuncture and Immunological Effects, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Planta Med. 2020 May;86(7):482-488. doi: 10.1055/a-1125-0385. Epub 2020 Mar 13.
Approximately 40% of compounds with therapeutic potential cannot be successfully developed into drugs owing to their poor pharmaceutical properties, emphasising the need to profile their drug-like properties as early as possible during preclinical development. This study aimed to evaluate the drug-like properties of ailanthone, a novel Chinese medicine monomer that was shown to have activity against castration-resistant prostate cancer tumour growth and metastasis in our previous study. The drug-like properties detected in the present study included effects on permeability, liver microsome stability, plasma protein binding rate, plasma stability, and human ether-à-go-go-related gene inhibition. Additionally, the following results were obtained: the efflux ratio of ailanthone was > 32 during permeability detection; the half-life and intrinsic clearance (Cl) in mouse, rat, and human liver microsomes were > 145 min and < 9.6 µL/min/mg protein, respectively. The Cl of ailanthone was < 38.0, < 17.3, and < 8.6 mL/min/kg body weight in mice, rats, and humans, respectively. The plasma protein binding percentage of ailanthone was 16.6 ± 4.2% in human plasma, with 62.5% remaining at 120 min after incubation. The IC value of ailanthone for the human ether-à-go-go-related gene channels was > 30 µM. Collectively, these results and those from our previous study indicate that the pharmacokinetic properties of ailanthone are suitable for the potential development of this compound as an oral or intravenous drug for the treatment of castration-resistant prostate cancer.
大约有 40%的具有治疗潜力的化合物由于其较差的药物性质而无法成功开发成药物，这强调了在临床前开发阶段尽早对其类药性进行评估的必要性。本研究旨在评估冬凌草甲素的类药性，冬凌草甲素是一种新型中药单体，在我们之前的研究中显示对去势抵抗性前列腺癌肿瘤生长和转移具有活性。本研究中检测到的类药性包括对通透性、肝微粒体稳定性、血浆蛋白结合率、血浆稳定性和人 Ether-à-go-go 相关基因抑制的影响。此外，还获得了以下结果：在通透性检测中，冬凌草甲素的外排比>32；在小鼠、大鼠和人肝微粒体中的半衰期和内在清除率（Cl）分别>145 分钟和<9.6µL/min/mg 蛋白。冬凌草甲素在小鼠、大鼠和人体内的 Cl 分别<38.0、<17.3 和<8.6mL/min/kg 体重。冬凌草甲素在人血浆中的蛋白结合率为 16.6±4.2%，孵育 120 分钟后仍有 62.5%的药物存在。冬凌草甲素对人 Ether-à-go-go 相关基因通道的 IC 值>30µM。综上所述，这些结果和我们之前的研究表明，冬凌草甲素的药代动力学性质适合将该化合物开发为口服或静脉注射药物，用于治疗去势抵抗性前列腺癌。
