Hallow K Melissa, Greasley Peter J, Heerspink Hiddo J L, Yu Hongtao
School of Chemical, Materials, and Biomedical Engineering, University of Georgia, Athens, GA, United States.
Department of Epidemiology and Biostatistics, University of Georgia, Athens, GA, United States.
Front Pharmacol. 2024 Nov 26;15:1332388. doi: 10.3389/fphar.2024.1332388. eCollection 2024.
Endothelin-1 (ET-1) regulates renal and vascular function, but the clinical utility of selective ET 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 ET receptor, either through increased ET-1 or non-selective ET.
A mathematical model of ET-1 kinetics was developed to quantify effects of ET antagonist exposure and selectivity on concentrations of ET-1 and its complexes with ET and ET receptors. The model describes ET-1 production, tissue and plasma distribution, ET and ET receptor binding, and receptor-mediated clearance, and was calibrated and validated with human ET-1 infusion studies.
The model confirmed the significant role of ET in ET-1 clearance. By varying both drug ET selectivity (K/K) and concentration over a wide range, simulations predicted that while selective ET antagonist (selectivity >1) always decreased [ET1-ET], the change in [ET1-ET] was more complex. It increased up to 45% as drug concentrations approached and exceeded K, 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-ET] was lower as ET selectivity decreased.
This is the first mechanistic mathematical model of ET-1 kinetics that describes receptor-mediated clearance, and the consequence of ET 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.
内皮素-1（ET-1）调节肾脏和血管功能，但由于相关的液体潴留，选择性ET受体拮抗剂的临床应用受到限制。液体潴留的潜在机制仍知之甚少，但可能是ET-1与未被拮抗的ET受体结合发生变化的结果，这可能是由于ET-1增加或非选择性ET所致。
建立了ET-1动力学的数学模型，以量化ET拮抗剂暴露和选择性对ET-1及其与ET和ET受体复合物浓度的影响。该模型描述了ET-1的产生、组织和血浆分布、ET与ET受体的结合以及受体介导的清除，并通过人体ET-1输注研究进行了校准和验证。
该模型证实了ET在ET-1清除中的重要作用。通过在很宽的范围内改变药物的ET选择性（K/K）和浓度，模拟预测，虽然选择性ET拮抗剂（选择性>1）总是降低[ET1-ET]，但[ET1-ET]的变化更为复杂。当药物浓度接近并超过K时，它增加高达45%，但随着药物浓度进一步增加并在高浓度时降至基线以下，增加幅度减小。导致[ET1-ET]降低所需的药物浓度随着ET选择性降低而降低。
这是第一个描述受体介导清除以及ET阻断对ET-1浓度影响的ET-1动力学机制数学模型。它提供了一个有用的工具，可以与实验研究相结合，以定量理解和研究这个复杂的动态系统。
