Characterization of structure and function of ZS-9, a K+ selective ion trap

• Published in: PloS one Vol. 9; no. 12; p. e114686
• Main Authors: Stavros, Fiona, Yang, Alex, Leon, Alejandro, Nuttall, Mark, Rasmussen, Henrik S
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 22.12.2014; Public Library of Science (PLoS)
• Subjects: Biology and Life Sciences; Calcium; Calcium - chemistry; Chemical composition; Gastrointestinal tract; Humans; Hydration; Hydrogen-Ion Concentration; Hyperkalemia; Hyperkalemia - drug therapy; Hyperkalemia - metabolism; Hyperkalemia - pathology; Intestine; Ion Exchange; Ion exchanging; Ions - chemistry; Kidney diseases; Laxatives; Magnesium; Medicine and Health Sciences; Morbidity; Mortality; Oral administration; Oxygen; pH effects; Physical Sciences; Polymers; Polystyrene; Polystyrene resins; Porosity; Potassium; Potassium - blood; Potassium - chemistry; Resins; Selectivity; Silica; Silicas; Silicates - chemistry; Silicates - therapeutic use; Sodium; Sodium - chemistry; Sodium polystyrene sulfonate; Structural analysis; Structure-function relationships; Zirconium; Zirconium compounds; Zirconium silicate
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0114686

Hyperkalemia, a condition in which serum potassium ions (K+) exceed 5.0 mmol/L, is a common electrolyte disorder associated with substantial morbidity. Current methods of managing hyperkalemia, including organic polymer resins such as sodium polystyrene sulfonate (SPS), are poorly tolerated and/or not effective. Sodium zirconium cyclosilicate (ZS-9) is under clinical development as an orally administered, non-absorbed, novel, inorganic microporous zirconium silicate compound that selectively removes excess K+ in vivo. The development, structure and ion exchange properties of ZS-9 and its hypothesized mechanism of action are described. Based on calculation of the interatomic distances between the atoms forming the ZS-9 micropores, the size of the pore opening was determined to be ∼ 3 Å (∼ diameter of unhydrated K+). Unlike nonspecific organic polymer resins like SPS, the ZS-9 K+ exchange capacity (KEC) was unaffected by the presence of calcium (Ca2+) or magnesium ions (Mg2+) and showed>25-fold selectivity for K+ over either Ca2+ or Mg2+. Conversely, the selectivity of SPS for K+ was only 0.2-0.3 times its selectivity for Ca2+ or Mg2+in mixed ionic media. It is hypothesized that the high K+ specificity of ZS-9 is attributable to the chemical composition and diameter of the micropores, which possibly act in an analogous manner to the selectivity filter utilized by physiologic K+ channels. This hypothesized mechanism of action is supported by the multi-ion exchange studies. The effect of pH on the KEC of ZS-9 was tested in different media buffered to mimic different portions of the human gastrointestinal tract. Rapid K+ uptake was observed within 5 minutes - mainly in the simulated small intestinal and large intestinal fluids, an effect that was sustained for up to 1 hour. If approved, ZS-9 will represent a novel, first-in-class therapy for hyperkalemia with improved capacity, selectivity, and speed for entrapping K+ when compared to currently available options.