title: Developing a Physiologically-Based Pharmacokinetic Model Knowledgebase in Support of Provisional Model Construction.
abstract: 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.
authors.affiliation: Oak Ridge Institute for Science and Education, Oak Ridge, Tennessee, United States of America.
authors.forename: Jingtao
authors.initials: J
authors.lastname: Lu
authors.affiliation: National Exposure Research Laboratory, US-Environmental Protection Agency, Research Triangle Park, North Carolina, United States of America.
authors.forename: Michael-Rock
authors.initials: MR
authors.lastname: Goldsmith
authors.affiliation: National Exposure Research Laboratory, US-Environmental Protection Agency, Research Triangle Park, North Carolina, United States of America.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Grulke
authors.affiliation: National Exposure Research Laboratory, US-Environmental Protection Agency, Research Triangle Park, North Carolina, United States of America.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Chang
authors.affiliation: National Exposure Research Laboratory, US-Environmental Protection Agency, Research Triangle Park, North Carolina, United States of America.
authors.forename: Raina D
authors.initials: RD
authors.lastname: Brooks
authors.affiliation: Oak Ridge Institute for Science and Education, Oak Ridge, Tennessee, United States of America.
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Leonard
authors.affiliation: Oak Ridge Institute for Science and Education, Oak Ridge, Tennessee, United States of America.
authors.forename: Martin B
authors.initials: MB
authors.lastname: Phillips
authors.affiliation: National Exposure Research Laboratory, US-Environmental Protection Agency, Research Triangle Park, North Carolina, United States of America.|Department of Environmental Engineering, North Carolina State University, Raleigh, North Carolina, United States of America.
authors.forename: Ethan D
authors.initials: ED
authors.lastname: Hypes
authors.affiliation: National Exposure Research Laboratory, US-Environmental Protection Agency, Research Triangle Park, North Carolina, United States of America.|Department of Physics and Physical Oceanography, University of North Carolina at Wilmington, Wilmington, North Carolina, United States of America.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Fair
authors.affiliation: National Exposure Research Laboratory, US-Environmental Protection Agency, Research Triangle Park, North Carolina, United States of America.
authors.forename: Rogelio
authors.initials: R
authors.lastname: Tornero-Velez
authors.affiliation: National Exposure Research Laboratory, US-Environmental Protection Agency, Las Vegas, Nevada, United States of America.
authors.forename: Jeffre
authors.initials: J
authors.lastname: Johnson
authors.affiliation: National Exposure Research Laboratory, US-Environmental Protection Agency, Las Vegas, Nevada, United States of America.
authors.forename: Curtis C
authors.initials: CC
authors.lastname: Dary
authors.affiliation: National Exposure Research Laboratory, US-Environmental Protection Agency, Research Triangle Park, North Carolina, United States of America.
authors.forename: Yu-Mei
authors.initials: YM
authors.lastname: Tan
mesh_terms: D000818:Animals; D019295:Computational Biology; D006801:Humans; D051188:Knowledge Bases; D051379:Mice; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010599:Pharmacokinetics; D051381:Rats; D013552:Swine
chemical_list: D004364:Pharmaceutical Preparations