Toward a general physiologically-based pharmacokinetic model for intravenously injected nanoparticles
Toward a general physiologically-based pharmacokinetic model for intravenously injected nanoparticles
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DOI：
10.2147/ijn.s94370
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发表时间：
2016-01-01
影响因子：
8
通讯作者：
Johanson, Gunnar
中科院分区：
文献类型：
--
作者：
Carlander, Ulrika;Li, Dingsheng;Johanson, Gunnar
为了评估纳米颗粒（NPs）的潜在毒性，有关其摄取和处置（生物动力学）的信息是必不可少的。工业化学品和药物的经验表明，生物动力学可以通过基于生理的药代动力学（PBPK）模型准确地描述和预测。迄今为止开发的纳米PBPK模型都涉及单一类型的NP。我们的目的是扩展聚乙二醇化聚丙烯酰胺NP的最新模型，以便为静脉注射到大鼠体内的不可降解NP开发更通用的PBPK模型。将相同的模型和生理参数应用于聚乙二醇化的聚丙烯酰胺、未包被的聚丙烯酰胺、金和二氧化钛的NP，而NP特异性参数的选择是基于最适合NP在各种组织中积累的实验时间过程。我们的模型充分描述了所有四种NPs的生物动力学行为，尽管这种行为以及它们的物理化学性质存在很大差异。此外，该模拟表明，剂量对生物动力学有深远的影响，因为在高剂量下吞噬细胞的饱和成为主要的限制步骤。对NP类型依赖性最大的拟合模型参数包括血：组织渗透系数和吞噬摄取速率常数。由于只使用了具有几种不同特征（剂量、大小、电荷、形状和表面性质）的四种NPs，因此无法阐明这些特征与np依赖模型参数之间的关系，因此需要更多的实验数据。在这方面，静脉内生物分布研究与相关的PBPK分析将提供最深入的见解。
To assess the potential toxicity of nanoparticles (NPs), information concerning their uptake and disposition (biokinetics) is essential. Experience with industrial chemicals and pharmaceutical drugs reveals that biokinetics can be described and predicted accurately by physiologically-based pharmacokinetic (PBPK) modeling. The nano PBPK models developed to date all concern a single type of NP. Our aim here was to extend a recent model for pegylated polyacrylamide NP in order to develop a more general PBPK model for nondegradable NPs injected intravenously into rats. The same model and physiological parameters were applied to pegylated polyacrylamide, uncoated polyacrylamide, gold, and titanium dioxide NPs, whereas NP-specific parameters were chosen on the basis of the best fit to the experimental time-courses of NP accumulation in various tissues. Our model describes the biokinetic behavior of all four types of NPs adequately, despite extensive differences in this behavior as well as in their physicochemical properties. In addition, this simulation demonstrated that the dose exerts a profound impact on the biokinetics, since saturation of the phagocytic cells at higher doses becomes a major limiting step. The fitted model parameters that were most dependent on NP type included the blood: tissue coefficients of permeability and the rate constant for phagocytic uptake. Since only four types of NPs with several differences in characteristics (dose, size, charge, shape, and surface properties) were used, the relationship between these characteristics and the NP-dependent model parameters could not be elucidated and more experimental data are required in this context. In this connection, intravenous biodistribution studies with associated PBPK analyses would provide the most insight.