一个主要的人类肠/肝微生理系统,用于估计人类口服生物可用性
Yassen Abbas1, Morné van Wyk1, Hailey Sze1
1CN Bio Innovations Ltd, Cambridge, United Kingdom.
概括
一个新的微生理系统 (MPS) 使用人类初级肠和肝细胞模拟口服药物吸收和新陈代谢. 该系统准确预测口服生物利用率及其成分,帮助药物开发.
科学领域:
- 药理动力学和药物新陈代谢
- 在体外建模和药物开发.
背景情况:
- 口服生物可用性对治疗药物疗效至关重要,受肠道吸收和第一通代谢的影响.
- 现有的体外模型缺乏完全描述肠道和肝脏对口服生物可用性的贡献的能力.
- 微生理系统 (MPSs) 为模拟复杂器官相互作用提供了一个有希望的方法.
研究的目的:
- 开发和验证一个主要的人类肠/肝微生理系统 (MPS) 用于药理动力学 (PK) 调查.
- 模拟口服和静脉注射的剂量路径,以评估药物的吸收和代谢.
- 在体外以机械方式建模人类口服生物利用率及其贡献因素 (Fa,Fg,Fh).
主要方法:
- 在共同培养中构建了一个MPS,包括初级人类阴上皮细胞和初级人类肝细胞.
- 整合了肠/肝 MPS 与 PK 参数估计的机械数学模型.
- 利用CYP3A基质米达佐拉姆来验证该系统模拟肠道和肝脏药物提取的能力.
主要成果:
- 主要的肠/肝 MPS 在共同培养中成功维持了肠和肝组织的功能.
- 综合系统准确估计了器官特异性PK参数和人类口服生物可用性.
- 证明了该系统能够机械地模拟口服化合物如米达佐拉姆的PKs的能力.
结论:
- 开发的初级肠/肝 MPS 提供了一种新的体外工具,以弥合肠道和肝脏对生物可用性的贡献.
- 该系统能够更准确地预测口服药物的性能,支持高效的药物发现和开发.
- 该MPS代表了对理解和优化口腔治疗的重大进步.
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