以生理学为基础的药理动力学模型用于评估N-二甲基胺 (NDMA) 的性别特异性暴露
Dong Wook Kang1, Ju Hee Kim1, Go-Wun Choi1
1College of Pharmacy, CHA University, 335 Pangyo-Ro, Bundang-Gu, Seongnam-Si, Gyeonggi-Do, 13488, Republic of Korea.
Archives of toxicology
|December 21, 2023
概括
这项研究开发了一种基于生理学的药理动力学 (PBPK) 模型,以了解大鼠对N-二甲基胺 (NDMA) 的暴露. 该模型将NDMA血度与毒性联系起来,有助于对人类致癌物暴露的风险评估.
科学领域:
- 毒理学 毒理学 毒理学
- 药理动力学 药理动力学
- 生物医学工程 生物医学工程
背景情况:
- N-二甲基胺 (NDMA) 是已知的人类致癌物,仅有有限的数据将暴露水平与毒性关联起来.
- 了解NDMA暴露与其对目标组织的影响之间的关系对于风险评估至关重要.
研究的目的:
- 在老鼠中开发和验证一种基于生理学的N-二甲基胺 (NDMA) 药理动力学 (PBPK) 模型.
- 评估性别特异性毒动力学,组织分布和NDMA的分泌.
- 为了建立在活体NDMA暴露与毒理效应相关的基础.
主要方法:
- 通过口服给大鼠3次NDMA剂量.
- 开发PBPK模型,包括主要目标组织 (血液,肠道,肝脏,脏,肺,心脏,大脑).
- 通过灵敏度分析,折叠误差和视觉检查进行模型验证;用于可变性评估的蒙特卡洛模拟.
主要成果:
- 一个经过验证的PBPK模型成功地开发了NDMA在老鼠.
- 该模型模拟了急性,中度和慢性持续时间的NDMA暴露.
- 评估了特定于性别的药理动力学和毒理动力学参数.
结论:
- 开发的PBPK模型提供了一个工具来估计与健康影响相关的NDMA血度范围.
- 这项研究为解释NDMA暴露与观察到的毒性之间的联系提供了科学基础.
- 这些发现支持对NDMA污染的风险评估和管理策略的改进.
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