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 (Clint) in mouse, rat, and human liver microsomes were > 145 min and < 9.6 µL/min/mg protein, respectively. The Clint(liver) 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 IC50 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.

中文翻译：

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确定具有抗 CRPC 活性的新型中药单体臭椿酮的类药物特性

大约 40% 的具有治疗潜力的化合物由于其较差的药物特性而无法成功开发成药物，这强调需要在临床前开发过程中尽早分析其类药特性。本研究旨在评估臭臭酮的类药物特性，臭臭酮是一种新型中药单体，在我们之前的研究中显示出对去势抵抗性前列腺癌肿瘤的生长和转移具有活性。本研究中检测到的类药物特性包括对渗透性、肝微粒体稳定性、血浆蛋白结合率、血浆稳定性和人类乙醚相关基因抑制的影响。此外，还得到了以下结果：渗透率检测过程中臭椿酮的外排比>32；小鼠、大鼠和人肝微粒体的半衰期和内在清除率 (Clint) 分别 > 145 分钟和 < 9.6 µL/min/mg 蛋白质。在小鼠、大鼠和人类中，臭椿酮的克林特（肝脏）分别为 < 38.0、< 17.3 和 < 8.6 mL/min/kg 体重。人血浆中臭椿酮的血浆蛋白结合百分比为 16.6 ± 4.2%，孵育 120 分钟后仍有 62.5%。臭椿酮对人类 ether-à-go-go 相关基因通道的 IC50 值 > 30 µM。总的来说，这些结果和我们之前研究的结果表明，臭葱酮的药代动力学特性适合将该化合物作为口服或静脉注射药物用于治疗去势抵抗性前列腺癌的潜在开发。分别为 145 分钟和 < 9.6 µL/分钟/mg 蛋白质。在小鼠、大鼠和人类中，臭椿酮的克林特（肝脏）分别为 < 38.0、< 17.3 和 < 8.6 mL/min/kg 体重。在人血浆中，臭葱酮的血浆蛋白结合百分比为 16.6 ± 4.2%，孵育 120 分钟后仍有 62.5%。臭椿酮对人类 ether-à-go-go 相关基因通道的 IC50 值 > 30 µM。总的来说，这些结果和我们之前研究的结果表明，臭葱酮的药代动力学特性适合将该化合物作为口服或静脉注射药物用于治疗去势抵抗性前列腺癌的潜在开发。分别为 145 分钟和 < 9.6 µL/分钟/mg 蛋白质。在小鼠、大鼠和人类中，臭椿酮的克林特（肝脏）分别为 < 38.0、< 17.3 和 < 8.6 mL/min/kg 体重。在人血浆中，臭葱酮的血浆蛋白结合百分比为 16.6 ± 4.2%，孵育 120 分钟后仍有 62.5%。臭椿酮对人类 ether-à-go-go 相关基因通道的 IC50 值 > 30 µM。总的来说，这些结果和我们之前研究的结果表明，臭葱酮的药代动力学特性适合将该化合物作为口服或静脉注射药物用于治疗去势抵抗性前列腺癌的潜在开发。分别。在人血浆中，臭葱酮的血浆蛋白结合百分比为 16.6 ± 4.2%，孵育 120 分钟后仍有 62.5%。臭椿酮对人类 ether-à-go-go 相关基因通道的 IC50 值 > 30 µM。总的来说，这些结果和我们之前研究的结果表明，臭葱酮的药代动力学特性适合将该化合物作为口服或静脉注射药物用于治疗去势抵抗性前列腺癌的潜在开发。分别。在人血浆中，臭葱酮的血浆蛋白结合百分比为 16.6 ± 4.2%，孵育 120 分钟后仍有 62.5%。臭椿酮对人类 ether-à-go-go 相关基因通道的 IC50 值 > 30 µM。总的来说，这些结果和我们之前研究的结果表明，臭葱酮的药代动力学特性适合将该化合物作为口服或静脉注射药物用于治疗去势抵抗性前列腺癌的潜在开发。