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Physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling of 3,3',4,4',5-pentachlorobiphenyl (PCB126)

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dc.contributor.authorLohitnavy, Manupat, author
dc.contributor.authorYang, Raymond H. S., advisor
dc.contributor.authorReisfeld, Brad, advisor
dc.date.accessioned2024-03-13T20:12:24Z
dc.date.available2024-03-13T20:12:24Z
dc.date.issued2008
dc.description.abstract3,3',4',4',5-Pentachlorobiphenyl (PCB126) is a persistent environment carcinogen. Despite its high lipophilicity, PCB126 was primarily recovered from liver. In addition, PCB126 could achieve its steady state in the liver in a relatively short period of time. Using a three-dimensional quantitative structure-activity relationship (3D-QSAR) model, PCB126 was predicted to be a Mrp2 substrate with a relatively high binding affinity (Km) value. With this newly emerging knowledge, we incorporated a Mrp2-mediated excretion process into our physiologically-based pharmacokinetic (PBPK) model of PCB126. Our model could describe numerous tissue concentration-time courses in different dosing conditions. Our PBPK model revealed an important role of Mrp2 in PCB126 disposition. In addition, to establish a correlation between PCB126 pharmacokinetics and its pharmacodynamic (PD) endpoint (i.e. hepatocarcinogenic effect), we used a chosen internal dose surrogate [i.e. area under the curve of PCB126 in liver (AUCLiver)] to predict the PD effect of PCB126. With this PBPK/PD model, correlation between the AUCLiver and our liver glutathione- S-transferase placental form positive (GSTP+) foci development data was demonstrated. We also conducted a pharmacokinetic interaction study between PCB126 and methotrexate (MTX), a known Mrp2 substrate, by exposing rats with multiple oral doses of PCB126 followed by an oral single dose of MTX. Liver samples were collected and analyzed for hepatic MTX and PCB126 concentration levels. Using a PBPK modeling technique incorporating with competitive inhibition processes between the two chemicals at the level of hepatic Mrp2, liver concentration-time courses of both chemicals were successfully simulated. To further investigate PD effects of PCB126 within liver GSTP + foci, we conducted an experiment by exposing rats with PCB126 using our modified liver foci bioassay up to 6 months. Liver foci positive or negative for GSTP+, transforming growth factor-α+ (TGFα+) and transforming growth factor-β Type 2 receptor (TGFβ2Rc-) were investigated. In rats treated with PCB126, time-dependent changes in all of three biomarkers were observed. Interestingly, when the GSTP+ foci were categorized into four phenotypic groups according to their TGFα and TGFβ2Rc expression, GSTP+ foci with TGFα expression and absence of TGFβ2Rc expression had significantly higher hepatocyte division rates than those of GSTP+ foci without TGFα expression and with TGFβ2Rc expression.
dc.format.mediumborn digital
dc.format.mediumdoctoral dissertations
dc.identifierETDF_Lohitnavy_2008_3321295.pdf
dc.identifier.urihttps://hdl.handle.net/10217/237852
dc.languageEnglish
dc.language.isoeng
dc.publisherColorado State University. Libraries
dc.relation.ispartof2000-2019
dc.rightsCopyright and other restrictions may apply. User is responsible for compliance with all applicable laws. For information about copyright law, please see https://libguides.colostate.edu/copyright.
dc.rights.licensePer the terms of a contractual agreement, all use of this item is limited to the non-commercial use of Colorado State University and its authorized users.
dc.subjectGSTP foci
dc.subjectmethotrexate
dc.subjectMrp2
dc.subjectPBPK/PD
dc.subjectPCB126
dc.subjectpentachlorobiphenyl
dc.subjectpharmacokinetics
dc.subjectpharmacology
dc.titlePhysiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling of 3,3',4,4',5-pentachlorobiphenyl (PCB126)
dc.typeText
dcterms.rights.dplaThis Item is protected by copyright and/or related rights (https://rightsstatements.org/vocab/InC/1.0/). You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s).
thesis.degree.disciplineEnvironmental and Radiological Health Sciences
thesis.degree.grantorColorado State University
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy (Ph.D.)

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