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首页> 外文期刊>Environmental Science & Technology >A Permeability-Limited Physiologically Based Pharmacokinetic (PBPK) Model for Perfluorooctanoic acid (PFOA) in Male Rats
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A Permeability-Limited Physiologically Based Pharmacokinetic (PBPK) Model for Perfluorooctanoic acid (PFOA) in Male Rats

机译：雄性大鼠全氟辛酸（PFOA）的基于渗透率的生理基础药代动力学（PBPK）模型

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摘要

Physiologically based pharmacokinetic (PBPK) modeling is a powerful in silico tool that can be used to simulate the toxicokinetics and tissue distribution of xenobiotic substances, such as perfluorooctanoic acid (PFOA), in organisms. However, most existing PBPK models have been based on the flow-limited assumption and largely rely on in vivo data for parametrization. In this study, we propose a permeability-limited PBPK model to estimate the toxicokinetics and tissue distribution of PFOA in male rats. Our model considers the cellular uptake and efflux of PFOA via both passive diffusion and transport facilitated by various membrane transporters, association with serum albumin in circulatory and extracellular spaces, and association with intracellular proteins in liver and kidney. Model performance is assessed using seven experimental data sets extracted from three different studies. Comparing model predictions with these experimental data, our model successfully predicts the toxicokinetics and tissue distribution of PFOA in rats following exposure via both IV and oral routes. More importantly, rather than requiring in vivo data fitting, all PFOA-related parameters were obtained from in vitro assays. Our model thus provides an effective framework to test in vitro-in vivo extrapolation and holds great promise for predicting toxicokinetics of per- and polyfluorinated alkyl substances in humans.
机译：基于生理的药代动力学（PBPK）建模是一种功能强大的计算机模拟工具，可用于模拟生物体中异生物素物质（例如全氟辛酸（PFOA））的毒物动力学和组织分布。但是，大多数现有的PBPK模型都是基于流量受限的假设，并且很大程度上依赖于体内数据进行参数化。在这项研究中，我们提出了一种通透性受限的PBPK模型，以评估雄性大鼠PFOA的毒代动力学和组织分布。我们的模型考虑了通过各种膜转运蛋白促进的被动扩散和转运，与循环和细胞外空间中的血清白蛋白的结合以及与肝和肾中细胞内蛋白的结合，PFOA的细胞摄取和流出。使用从三个不同研究中提取的七个实验数据集来评估模型性能。通过将模型预测结果与这些实验数据进行比较，我们的模型成功地预测了通过静脉和口服途径暴露后大鼠中PFOA的毒代动力学和组织分布。更重要的是，无需进行体内数据拟合，所有与PFOA相关的参数都可以通过体外测定获得。因此，我们的模型为测试体外-体内外推提供了有效的框架，并为预测人体内全氟化和多氟化烷基物质的毒物动力学具有广阔的前景。

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  • 来源
    《Environmental Science & Technology》 |2017年第17期|9930-9939|共10页
  • 作者

    Weixiao Cheng; Carla A. Ng;

  • 作者单位

    Department of Civil and Environmental Engineering, University of Pittsburgh, 3700 O'Hara Street, Pittsburgh, Pennsylvania 15261, United States;

    Department of Civil and Environmental Engineering, University of Pittsburgh, 3700 O'Hara Street, Pittsburgh, Pennsylvania 15261, United States;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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