Department of Environmental and Global Health, College of Public Health and Health Professions, University of Florida, 1225 Center Drive, Gainesville, FL, 32610, USA.
Center for Environmental and Human Toxicology, University of Florida, Gainesville, FL, 32608, USA.
Part Fibre Toxicol. 2022 Jul 8;19(1):47. doi: 10.1186/s12989-022-00489-4.
Physiologically based pharmacokinetic (PBPK) modeling is an important tool in predicting target organ dosimetry and risk assessment of nanoparticles (NPs). The methodology of building a multi-route PBPK model for NPs has not been established, nor systematically evaluated. In this study, we hypothesized that the traditional route-to-route extrapolation approach of PBPK modeling that is typically used for small molecules may not be appropriate for NPs. To test this hypothesis, the objective of this study was to develop a multi-route PBPK model for different sizes (1.4-200 nm) of gold nanoparticles (AuNPs) in adult rats following different routes of administration (i.e., intravenous (IV), oral gavage, intratracheal instillation, and endotracheal inhalation) using two approaches: a traditional route-to-route extrapolation approach for small molecules and a new approach that is based on route-specific data that we propose to be applied generally to NPs.
We found that the PBPK model using this new approach had superior performance than the traditional approach. The final PBPK model was optimized rigorously using a Bayesian hierarchical approach with Markov chain Monte Carlo simulations, and then converted to a web-based interface using R Shiny. In addition, quantitative structure-activity relationships (QSAR) based multivariate linear regressions were established to predict the route-specific key biodistribution parameters (e.g., maximum uptake rate) based on the physicochemical properties of AuNPs (e.g., size, surface area, dose, Zeta potential, and NP numbers). These results showed the size and surface area of AuNPs were the main determinants for endocytic/phagocytic uptake rates regardless of the route of administration, while Zeta potential was an important parameter for the estimation of the exocytic release rates following IV administration.
This study suggests that traditional route-to-route extrapolation approaches for PBPK modeling of small molecules are not applicable to NPs. Therefore, multi-route PBPK models for NPs should be developed using route-specific data. This novel PBPK-based web interface serves as a foundation for extrapolating to other NPs and to humans to facilitate biodistribution estimation, safety, and risk assessment of NPs.
生理药代动力学（PBPK）模型是预测纳米颗粒（NPs）靶器官剂量和风险评估的重要工具。尚未建立构建 NPs 多途径 PBPK 模型的方法学，也未对其进行系统评估。在本研究中，我们假设 PBPK 建模中传统的从途径到途径的外推方法通常不适用于小分子，也不适用于 NPs。为了验证这一假设，本研究的目的是使用两种方法，即传统的小分子从途径到途径的外推方法和我们建议一般适用于 NPs 的基于途径特异性数据的新方法，为不同大小（1.4-200nm）的金纳米颗粒（AuNPs）在成年大鼠中经不同途径（即静脉内（IV）、口服灌胃、气管内滴注和气管内吸入）建立多途径 PBPK 模型。
我们发现，使用新方法的 PBPK 模型具有优于传统方法的性能。最终的 PBPK 模型使用贝叶斯分层方法和马尔可夫链蒙特卡罗模拟进行了严格优化，并使用 R Shiny 转换为基于网络的界面。此外，建立了定量构效关系（QSAR）多元线性回归，以根据 AuNPs 的物理化学性质（如大小、表面积、剂量、Zeta 电位和 NP 数量）预测途径特异性关键生物分布参数（如最大摄取率）。这些结果表明，无论给药途径如何，AuNPs 的大小和表面积是内吞/吞噬摄取率的主要决定因素，而 Zeta 电位是 IV 给药后外排释放率估计的重要参数。
本研究表明，小分子 PBPK 建模的传统从途径到途径的外推方法不适用于 NPs。因此，应使用途径特异性数据开发 NPs 的多途径 PBPK 模型。这个新的基于 PBPK 的网络界面可作为外推到其他 NPs 和人类的基础，以促进 NPs 的生物分布评估、安全性和风险评估。
