Complexation\nBehavior and Clinical Assessment of Isomeric\nCalcium Ionophores of ETH 1001 in Polymeric Ion-Selective Membranes

Calcium\nions are crucial in numerous physiological processes,\nand\ntheir precise measurement is important for many clinical diagnostics\nand therapeutic interventions. Traditional detection methods, such\nas atomic absorption spectroscopy, cannot meet clinical requirements,\nas they measure total calcium instead of the clinically relevant ionized\nform (Ca<sup>2+</sup>). Ion-selective electrodes (ISEs) provide a\nconvenient, accurate, and specific method for Ca<sup>2+</sup> determination.\nHere, two isomeric calcium ionophores (<i>R</i>,<i>R</i>)-calcium ionophore I, also known as ETH 1001, and (<i>R</i>,<i>S</i>)-calcium ionophore I are synthesized\nand characterized for the analysis of whole blood samples with the\nEaglenos blood gas analyzer (model: EG-i30) equipped with test cartridges\ncontaining screen-printed electrodes. (<i>R</i>,<i>R</i>)-Calcium ionophore I demonstrated excellent precision\nin whole blood samples, achieving an average bias of −2.2%\ncompared with the available gold standard. On the other hand, the\n(<i>R</i>,<i>S</i>) isomer was not satisfactory,\nexhibiting a bias of up to −20%. Ion transfer voltammetry at\nthin membrane films gave information about the complex stoichiometry,\ncomplex formation constants, and ion selectivity for the two isomeric\nionophores. A stoichiometry of the Ca<sup>2+</sup>-ionophore complex\nwas confirmed to be 1:2 for both ionophores, while the (<i>R</i>,<i>R</i>) isomer gave 3.4 orders of magnitude larger complex\nformation constants and a modestly higher selectivity. While these\ndata are valuable, the poor performance of membranes containing the\n(<i>R</i>,<i>S</i>) isomer is not directly apparent\nfrom the fundamental binding characteristics. It may be caused by\ninterference from lipophilic blood sample components and/or surface\nadsorption processes, suggesting that routine selectivity characterizations\nof membranes containing selective ionophores are insufficient to assess\ntheir usefulness in clinical applications.