Ramboll Environment and Health Consulting, 3214 Charles B. Root Wynd Suite 130, Raleigh, NC 27612, USA.
Syngenta Ltd, Jealott's Hill International Research Centre, Bracknell, Berkshire RG42 6EY, UK.
Toxicol Appl Pharmacol. 2021 Apr 15;417:115462. doi: 10.1016/j.taap.2021.115462. Epub 2021 Feb 22.
Paraquat dichloride (PQ) is a non-selective herbicide which has been the subject of numerous toxicology studies over more than 50 years. This paper describes the development of a physiologically-based pharmacokinetic (PBPK) model of PQ kinetics for the rat, mouse and dog, firstly to aid the interpretation of studies in which no kinetic measurements were made, and secondly to enable the future extension of the model to humans. Existing pharmacokinetic data were used to develop a model for the rat and mouse. Simulations with this preliminary model were then used to identify key data gaps and to design a new blood binding study to reduce uncertainty in critical aspects of the model. The new data provided evidence to support the model structure, and its predictive performance was then assessed against dog and rat datasets not used in model development. The PQ-specific model parameters are the same for all three species, with only the physiological parameters varying between species. This consistency across species provides a strong basis for extrapolation to other species, as demonstrated here for the dog. The model enables a wide range of PQ data to be linked together to provide a broad understanding of PQ pharmacokinetics in rodents and the dog, showing that the key aspects of PQ kinetics in these species are understood and adequately encapsulated within the model.
敌草快二氯盐（PQ）是一种非选择性除草剂，50 多年来已进行了大量毒理学研究。本文描述了大鼠、小鼠和犬敌草快动力学的生理相关药代动力学（PBPK）模型的开发，其目的首先是帮助解释未进行动力学测量的研究，其次是能够将来将模型扩展到人类。使用现有的药代动力学数据来开发大鼠和小鼠的模型。使用该初步模型进行模拟，然后确定关键数据差距，并设计新的血液结合研究，以减少模型中关键方面的不确定性。新数据为模型结构提供了证据支持，然后根据未用于模型开发的犬和大鼠数据集评估其预测性能。PQ 特异性模型参数在所有三种物种中相同，只有生理参数在物种之间有所不同。这种跨物种的一致性为其他物种的推断提供了坚实的基础，正如本文在犬中的演示。该模型能够将广泛的 PQ 数据联系在一起，从而广泛了解啮齿动物和犬的 PQ 药代动力学，表明这些物种中 PQ 动力学的关键方面已被理解并在模型中得到充分体现。
