通过局部应用,通过ADME表征和PBK模型开发3种高度与蛋白质结合的紫外线过器
Hequn Li1, Fazila Bunglawala1, Nicola J Hewitt2
1Unilever Safety and Environmental Assurance Centre, Sharnbrook MK44 1LQ, UK.
概括
基于生理学的动力学 (PBK) 模型被开发为三个UV过器使用体外和体内数据. 这些模型准确地预测了人类的暴露,支持化学安全评估,而不需要对人类进行广泛的测试.
科学领域:
- 毒理学和化学安全评估
- 药理动力学和计算机建模
背景情况:
- 准确估计人类暴露对于化学品安全评估至关重要.
- 基于生理学的动力学 (PBK) 模型整合了暴露,生理学和化学数据,以预测内部化学暴露.
- 紫外线过器对传统测试提出了挑战,因为它们具有脂性和结合性.
研究的目的:
- 开发和验证三种常见的紫外线过器的PBK模型:八甲基酸盐,八烯和4-甲基利丁.
- 为了证明一个自下而上的建模方法,仅使用体外和体内数据.
- 在人类药物动力学数据有限的情况下,加强对使用PBK建模进行安全决策的信心.
主要方法:
- 使用自下而上的方法为三个紫外线过器开发PBK模型.
- 模型的参数化仅基于 in vitro 和/或 in silico 数据.
- 开发的PBK模型与人类皮肤药理动力学数据的验证.
主要成果:
- 开发的PBK模型成功地模拟了皮肤应用后从临床药理动力学数据中获得的血度概况.
- 这些模型证明了通过体外/in silico方法生成的ADME数据和确定参数的可靠性.
- 这项研究突出了产生和解释ADME数据对具有挑战性的化学品的关键考虑因素.
结论:
- 可靠地开发PBK模型,仅使用UV过器的in vitro和in silico数据.
- 经过验证的PBK模型通过准确预测内部暴露来支持化学安全评估.
- 这些发现为在未来的风险评估中建模高度脂性和蛋白质结合的化学物质提供了宝贵的见解.
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