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基于贝叶斯方法对大鼠体内金属纳米颗粒长期动力学的生理药代动力学(PBPK)模型的评估。

Bayesian evaluation of a physiologically-based pharmacokinetic (PBPK) model of long-term kinetics of metal nanoparticles in rats.

作者信息

Sweeney Lisa M, MacCalman Laura, Haber Lynne T, Kuempel Eileen D, Tran C Lang

机构信息

Henry M. Jackson Foundation for the Advancement of Military Medicine, Naval Medical Research Unit Dayton (NAMRU Dayton), 2729 R Street, Building 837, Wright Patterson Air Force Base, OH 45433, USA; Toxicology Excellence for Risk Assessment (TERA), 2300 Montana Avenue, Cincinnati, OH 45211, USA.

Institute of Occupational Medicine, Research Avenue North, Riccarton, Edinburgh EH14 4AP, UK.

出版信息

Regul Toxicol Pharmacol. 2015 Oct;73(1):151-63. doi: 10.1016/j.yrtph.2015.06.019. Epub 2015 Jul 3.

Abstract

Biomathematical modeling quantitatively describes the disposition of metal nanoparticles in lungs and other organs of rats. In a preliminary model, adjustable parameters were calibrated to each of three data sets using a deterministic approach, with optimal values varying among the different data sets. In the current effort, Bayesian population analysis using Markov chain Monte Carlo (MCMC) simulation was used to recalibrate the model while improving assessments of parameter variability and uncertainty. The previously-developed model structure and some physiological parameter values were modified to improve physiological realism. The data from one of the three previously-identified studies and from two other studies were used for model calibration. The data from the one study that adequately characterized mass balance were used to generate parameter distributions. When data from a second study of the same nanomaterial (iridium) were added, the level of agreement was still acceptable. Addition of another data set (for silver nanoparticles) led to substantially lower precision in parameter estimates and large discrepancies between the model predictions and experimental data for silver nanoparticles. Additional toxicokinetic data are needed to further evaluate the model structure and performance and to reduce uncertainty in the kinetic processes governing in vivo disposition of metal nanoparticles.

摘要

生物数学建模定量描述了金属纳米颗粒在大鼠肺部和其他器官中的分布情况。在一个初步模型中,使用确定性方法针对三个数据集分别校准了可调参数,不同数据集的最优值各不相同。在当前的研究中,采用马尔可夫链蒙特卡罗(MCMC)模拟的贝叶斯群体分析方法对模型进行重新校准,同时改进对参数变异性和不确定性的评估。对先前开发的模型结构和一些生理参数值进行了修改,以提高生理真实性。来自先前确定的三项研究中的一项以及另外两项研究的数据用于模型校准。来自一项充分表征质量平衡的研究的数据用于生成参数分布。当添加来自同一纳米材料(铱)的第二项研究的数据时,一致性水平仍然可以接受。添加另一个数据集(用于银纳米颗粒)导致参数估计的精度大幅降低,并且银纳米颗粒的模型预测与实验数据之间存在很大差异。需要更多的毒代动力学数据来进一步评估模型结构和性能,并减少控制金属纳米颗粒体内分布的动力学过程中的不确定性。

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