Kinetics of endothelin-1 and effect selective ETA antagonism on ETB activation: a mathematical modeling analysis
IntroductionEndothelin-1 (ET-1) regulates renal and vascular function, but the clinical utility of selective ETA receptor antagonists has been limited due to associated fluid retention. The mechanisms underlying fluid retention remain poorly understood but could be a consequence of changes in ET-1 b...
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Frontiers Media S.A.
2024-11-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2024.1332388/full |
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| author | K. Melissa Hallow K. Melissa Hallow Peter J. Greasley Hiddo J. L. Heerspink Hiddo J. L. Heerspink Hongtao Yu |
| author_facet | K. Melissa Hallow K. Melissa Hallow Peter J. Greasley Hiddo J. L. Heerspink Hiddo J. L. Heerspink Hongtao Yu |
| author_sort | K. Melissa Hallow |
| collection | DOAJ |
| description | IntroductionEndothelin-1 (ET-1) regulates renal and vascular function, but the clinical utility of selective ETA receptor antagonists has been limited due to associated fluid retention. The mechanisms underlying fluid retention remain poorly understood but could be a consequence of changes in ET-1 binding to the unantagonized ETB receptor, either through increased ET-1 or non-selective ETB.MethodsA mathematical model of ET-1 kinetics was developed to quantify effects of ETA antagonist exposure and selectivity on concentrations of ET-1 and its complexes with ETA and ETB receptors. The model describes ET-1 production, tissue and plasma distribution, ETA and ETB receptor binding, and receptor-mediated clearance, and was calibrated and validated with human ET-1 infusion studies.ResultsThe model confirmed the significant role of ETB in ET-1 clearance. By varying both drug ETA selectivity (Kib/Kia) and concentration over a wide range, simulations predicted that while selective ETA antagonist (selectivity >1) always decreased [ET1-ETA], the change in [ET1-ETB] was more complex. It increased up to 45% as drug concentrations approached and exceeded Kia, but the increase was diminished as drug concentration increased further and fell below baseline at high concentrations. The drug concentration required to cause a decrease in [ET1-ETB] was lower as ETA selectivity decreased.DiscussionThis is the first mechanistic mathematical model of ET-1 kinetics that describes receptor-mediated clearance, and the consequence of ETB blockade on ET-1 concentrations. It provides a useful tool that can coupled with experimental studies to quantitively understand and investigate this complex and dynamic system. |
| format | Article |
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| issn | 1663-9812 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj-art-35527bed2919432ba86cbe10281ef2482025-08-20T01:53:31ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122024-11-011510.3389/fphar.2024.13323881332388Kinetics of endothelin-1 and effect selective ETA antagonism on ETB activation: a mathematical modeling analysisK. Melissa Hallow0K. Melissa Hallow1Peter J. Greasley2Hiddo J. L. Heerspink3Hiddo J. L. Heerspink4Hongtao Yu5School of Chemical, Materials, and Biomedical Engineering, University of Georgia, Athens, GA, United StatesDepartment of Epidemiology and Biostatistics, University of Georgia, Athens, GA, United StatesEarly Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), Biopharmaceuticals, R&D, AstraZeneca, Gothenburg, SwedenDepartment of Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, NetherlandsThe George Institute for Global Health, Sydney, AustraliaClinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gaithersburg, MD, United StatesIntroductionEndothelin-1 (ET-1) regulates renal and vascular function, but the clinical utility of selective ETA receptor antagonists has been limited due to associated fluid retention. The mechanisms underlying fluid retention remain poorly understood but could be a consequence of changes in ET-1 binding to the unantagonized ETB receptor, either through increased ET-1 or non-selective ETB.MethodsA mathematical model of ET-1 kinetics was developed to quantify effects of ETA antagonist exposure and selectivity on concentrations of ET-1 and its complexes with ETA and ETB receptors. The model describes ET-1 production, tissue and plasma distribution, ETA and ETB receptor binding, and receptor-mediated clearance, and was calibrated and validated with human ET-1 infusion studies.ResultsThe model confirmed the significant role of ETB in ET-1 clearance. By varying both drug ETA selectivity (Kib/Kia) and concentration over a wide range, simulations predicted that while selective ETA antagonist (selectivity >1) always decreased [ET1-ETA], the change in [ET1-ETB] was more complex. It increased up to 45% as drug concentrations approached and exceeded Kia, but the increase was diminished as drug concentration increased further and fell below baseline at high concentrations. The drug concentration required to cause a decrease in [ET1-ETB] was lower as ETA selectivity decreased.DiscussionThis is the first mechanistic mathematical model of ET-1 kinetics that describes receptor-mediated clearance, and the consequence of ETB blockade on ET-1 concentrations. It provides a useful tool that can coupled with experimental studies to quantitively understand and investigate this complex and dynamic system.https://www.frontiersin.org/articles/10.3389/fphar.2024.1332388/fullendothelinendothelin receptor antagonistmathematical modelingkineticsETAETB |
| spellingShingle | K. Melissa Hallow K. Melissa Hallow Peter J. Greasley Hiddo J. L. Heerspink Hiddo J. L. Heerspink Hongtao Yu Kinetics of endothelin-1 and effect selective ETA antagonism on ETB activation: a mathematical modeling analysis Frontiers in Pharmacology endothelin endothelin receptor antagonist mathematical modeling kinetics ETA ETB |
| title | Kinetics of endothelin-1 and effect selective ETA antagonism on ETB activation: a mathematical modeling analysis |
| title_full | Kinetics of endothelin-1 and effect selective ETA antagonism on ETB activation: a mathematical modeling analysis |
| title_fullStr | Kinetics of endothelin-1 and effect selective ETA antagonism on ETB activation: a mathematical modeling analysis |
| title_full_unstemmed | Kinetics of endothelin-1 and effect selective ETA antagonism on ETB activation: a mathematical modeling analysis |
| title_short | Kinetics of endothelin-1 and effect selective ETA antagonism on ETB activation: a mathematical modeling analysis |
| title_sort | kinetics of endothelin 1 and effect selective eta antagonism on etb activation a mathematical modeling analysis |
| topic | endothelin endothelin receptor antagonist mathematical modeling kinetics ETA ETB |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2024.1332388/full |
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