Kinetics of endothelin-1 and effect selective ET antagonism on ET activation: a mathematical modeling analysis.

INTRODUCTION

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.

METHODS

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.

RESULTS

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.

DISCUSSION

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.