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DOI10.1371/journal.pcbi.1004495
Developing a Physiologically-Based Pharmacokinetic Model Knowledgebase in Support of Provisional Model Construction
Lu, Jingtao1; Goldsmith, Michael-Rock2,6; Grulke, Christopher M.2,7; Chang, Daniel T.2,6; Brooks, Raina D.2,8; Leonard, Jeremy A.1; Phillips, Martin B.1,9; Hypes, Ethan D.2,3; Fair, Matthew J.2,4; Tornero-Velez, Rogelio2; Johnson, Jeffre5; Dary, Curtis C.5,10; Tan, Yu-Mei2
发表日期2016-02-01
ISSN1553-734X
卷号12期号:2
英文摘要

Developing physiologically-based pharmacokinetic (PBPK) models for chemicals can be resource-intensive, as neither chemical-specific parameters nor in vivo pharmacokinetic data are easily available for model construction. Previously developed, well-parameterized, and thoroughly-vetted models can be a great resource for the construction of models pertaining to new chemicals. A PBPK knowledgebase was compiled and developed from existing PBPK-related articles and used to develop new models. From 2,039 PBPK-related articles published between 1977 and 2013, 307 unique chemicals were identified for use as the basis of our knowledgebase. Keywords related to species, gender, developmental stages, and organs were analyzed from the articles within the PBPK knowledgebase. A correlation matrix of the 307 chemicals in the PBPK knowledgebase was calculated based on pharmacokinetic-relevant molecular descriptors. Chemicals in the PBPK knowledgebase were ranked based on their correlation toward ethylbenzene and gefitinib. Next, multiple chemicals were selected to represent exact matches, close analogues, or non-analogues of the target case study chemicals. Parameters, equations, or experimental data relevant to existing models for these chemicals and their analogues were used to construct new models, and model predictions were compared to observed values. This compiled knowledgebase provides a chemical structure-based approach for identifying PBPK models relevant to other chemical entities. Using suitable correlation metrics, we demonstrated that models of chemical analogues in the PBPK knowledgebase can guide the construction of PBPK models for other chemicals.


语种英语
WOS记录号WOS:000376582900020
来源期刊PLOS COMPUTATIONAL BIOLOGY
来源机构美国环保署
文献类型期刊论文
条目标识符http://gcip.llas.ac.cn/handle/2XKMVOVA/61673
作者单位1.Oak Ridge Inst Sci & Educ, Oak Ridge, TN USA;
2.US EPA, Natl Exposure Res Lab, Res Triangle Pk, NC 27711 USA;
3.N Carolina State Univ, Dept Environm Engn, Raleigh, NC 27695 USA;
4.Univ N Carolina, Dept Phys & Phys Oceanog, Wilmington, NC 28401 USA;
5.US EPA, Natl Exposure Res Lab, Las Vegas, NV 89193 USA;
6.Chem Comp Grp, Montreal, PQ, Canada;
7.Lockheed Martin, Res Triangle Pk, NC USA;
8.Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL USA;
9.Minnesota Dept Hlth, St Paul, MN USA;
10.Insiliconomics, Birchwood, WI USA
推荐引用方式
GB/T 7714
Lu, Jingtao,Goldsmith, Michael-Rock,Grulke, Christopher M.,et al. Developing a Physiologically-Based Pharmacokinetic Model Knowledgebase in Support of Provisional Model Construction[J]. 美国环保署,2016,12(2).
APA Lu, Jingtao.,Goldsmith, Michael-Rock.,Grulke, Christopher M..,Chang, Daniel T..,Brooks, Raina D..,...&Tan, Yu-Mei.(2016).Developing a Physiologically-Based Pharmacokinetic Model Knowledgebase in Support of Provisional Model Construction.PLOS COMPUTATIONAL BIOLOGY,12(2).
MLA Lu, Jingtao,et al."Developing a Physiologically-Based Pharmacokinetic Model Knowledgebase in Support of Provisional Model Construction".PLOS COMPUTATIONAL BIOLOGY 12.2(2016).
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