Sluka James P, Fu Xiao, Swat Maciej, Belmonte Julio M, Cosmanescu Alin, Clendenon Sherry G, Wambaugh John F, Glazier James A
Biocomplexity Institute Indiana University Bloomington, Bloomington, IN 47405-7105, United States of America.
National Center for Computational Toxicology Office of Research and Development US EPA, Research Triangle Park, NC 27711, United States of America.
PLoS One. 2016 Sep 16;11(9):e0162428. doi: 10.1371/journal.pone.0162428. eCollection 2016.
We describe a multi-scale, liver-centric in silico modeling framework for acetaminophen pharmacology and metabolism. We focus on a computational model to characterize whole body uptake and clearance, liver transport and phase I and phase II metabolism. We do this by incorporating sub-models that span three scales; Physiologically Based Pharmacokinetic (PBPK) modeling of acetaminophen uptake and distribution at the whole body level, cell and blood flow modeling at the tissue/organ level and metabolism at the sub-cellular level. We have used standard modeling modalities at each of the three scales. In particular, we have used the Systems Biology Markup Language (SBML) to create both the whole-body and sub-cellular scales. Our modeling approach allows us to run the individual sub-models separately and allows us to easily exchange models at a particular scale without the need to extensively rework the sub-models at other scales. In addition, the use of SBML greatly facilitates the inclusion of biological annotations directly in the model code. The model was calibrated using human in vivo data for acetaminophen and its sulfate and glucuronate metabolites. We then carried out extensive parameter sensitivity studies including the pairwise interaction of parameters. We also simulated population variation of exposure and sensitivity to acetaminophen. Our modeling framework can be extended to the prediction of liver toxicity following acetaminophen overdose, or used as a general purpose pharmacokinetic model for xenobiotics.
我们描述了一种用于对乙酰氨基酚药理学和代谢的多尺度、以肝脏为中心的计算机模拟框架。我们专注于一个计算模型，以表征全身摄取和清除、肝脏转运以及I相和II相代谢。我们通过纳入跨越三个尺度的子模型来实现这一点；在全身水平上对乙酰氨基酚摄取和分布进行基于生理学的药代动力学（PBPK）建模，在组织/器官水平上进行细胞和血流建模，以及在亚细胞水平上进行代谢建模。我们在这三个尺度中的每一个上都使用了标准的建模方式。特别是，我们使用系统生物学标记语言（SBML）来创建全身和亚细胞尺度的模型。我们的建模方法使我们能够分别运行各个子模型，并使我们能够在特定尺度上轻松交换模型，而无需对其他尺度的子模型进行大量返工。此外，SBML的使用极大地促进了直接在模型代码中纳入生物学注释。该模型使用了关于乙酰氨基酚及其硫酸盐和葡萄糖醛酸代谢物的人体体内数据进行校准。然后，我们进行了广泛的参数敏感性研究，包括参数的成对相互作用。我们还模拟了人群对乙酰氨基酚暴露和敏感性的变化。我们的建模框架可以扩展到预测乙酰氨基酚过量后的肝毒性，或用作外源性物质的通用药代动力学模型。
