目标储备和营业额参数 确定埃纳拉普利拉特功能的向右转移,从其与血管素转化酶的结合关系向右转移
Van Anh Nguyen1, Li Zhang1, Leonid Kagan2
1Department of Pharmaceutical Sciences, University at Buffalo, the State University of New York, Buffalo, NY, USA.
Journal of pharmaceutical sciences
|October 23, 2023
概括
这项研究开发了埃纳拉普利拉特的模型,显示药物强度 (IC50) 可能因目标储备等因素而不同于向药物处置 (TMDD) 中的结合亲和力 (KD).
科学领域:
- 药理学 药理学是指药理学的学科.
- 药理动力学 药理动力学
- 生物标志物 生物标志物
背景情况:
- 药物效应通常被认为与目标占用率成正比.
- 目标介导药物排放 (TMDD) 可能导致药物结合亲和力和效力之间的差异.
- 像伊纳拉普利拉特这样的 ангиотензин转化酶 (ACE) 抑制剂是表现为TMDD的药物的例子.
研究的目的:
- 开发一个药理动力学/药理动力学模型,用于人类的埃纳拉普利拉特.
- 评估ex vivo药物强度 (IC50) 和体内标结合亲和力 (KD) 之间的关系.
- 为理解TMDD药物行为提供理论框架.
主要方法:
- 开发了埃纳拉普利拉特的药理动力学/药理动力学模型.
- 包括抗胰岛素I和埃纳拉普利拉特对ACE的竞争性结合.
- 考虑了流通的目标池,并使用文献数据进行模型装配.
- 在体内估计的KD,总目标密度和循环目标的部分.
主要成果:
- 该模型充分表征了埃纳拉普利拉特度和氨酸 - 血管新生素系统生物标志物.
- 在体内估计的KD为0.646nM,总目标密度为32.0nM.
- 与KD相比,模型模拟预测IC50增加了6.3倍.
- 目标储备和降解被确定为影响从结合亲和力转变为功效的关键因素.
结论:
- 药物强度 (IC50) 可以显著高于体内结合亲和力 (KD) 的药物与TMDD.
- 目标储备和降解影响着结合亲和力和强度之间的关系.
- 这些发现对药物开发和将结合 afinity 转化为治疗功效有意义.
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