在大鼠血中使用givinostat的UPLC-MS/MS方法:开发,验证,体内药理动力学研究和体内代谢稳定性研究
Ruanjuan Zhan1, Yanan Liu1,2, Jun Wu1,2
1The First Affiliated Hospital of Wenzhou Medical University, Zhejiang, People's Republic of China.
Drug design, development and therapy
|January 20, 2025
概括
吉维诺斯塔特是一种有前途的白血病HDAC抑制剂,在老鼠中被迅速吸收并缓慢清除. 这项研究开发了一种用于测量givinostat的快速分析方法,有助于其临床前和临床发展.
科学领域:
- 药理学 药理学是指药理学的学科.
- 分析化学 分析化学
- 生物化学 生物化学
背景情况:
- 吉维诺斯塔特是一种强效的基因素脱乙酶 (HDAC) 抑制剂,具有治疗复发性白血病和骨髓瘤的治疗潜力.
- 了解givinostat的药理动力学和代谢特征对于其临床应用至关重要.
研究的目的:
- 开发和验证用于量化givinostat度的快速试验.
- 在临床前模型中建立givinostat的初步药理动力学概况.
- 为了评估givinostat的体外代谢稳定性.
主要方法:
- 超高性能液态染色体协同质谱法 (UPLC-MS/MS) 用于givinostat测量.
- 埃利格斯图特 (Eliglustat) 作为检测量量的内部标准 (IS).
- 用蛋白沉进行样本制备,然后在C18柱上进行梯度化.
主要成果:
- 在UPLC-MS/MS试验中,在广泛的度范围 (24000 ng/mL) 上显示出优异的线性 (r2=0.998).
- 该方法表现出高精度 (95.8%-108.6%) 和精度 (RSD% <15%),超过90%的回收率和最小的矩阵效应.
- 鼠类的药理动力学研究显示,吉维诺斯塔特的吸收速度快,清除速度缓慢,体外半衰期为92.87分钟,内在清除速度缓慢.
结论:
- 吉维诺斯塔特在体内被快速吸收并缓慢排出,这与体外代谢稳定性研究结果一致.
- 开发的UPLC-MS/MS测定适用于givinostat的临床前药理动力学研究.
- 这项研究提供了有价值的数据,以支持givinostat的正在进行的临床开发.
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