Characterization of structure and function of ZS-9, a K+ selective ion trap.
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 n...
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Public Library of Science (PLoS)
2014-01-01
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| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0114686&type=printable |
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| author | Fiona Stavros Alex Yang Alejandro Leon Mark Nuttall Henrik S Rasmussen |
| author_facet | Fiona Stavros Alex Yang Alejandro Leon Mark Nuttall Henrik S Rasmussen |
| author_sort | Fiona Stavros |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-37cee8f25ef5433ebff1a80e044b0272 |
| institution | OA Journals |
| issn | 1932-6203 |
| language | English |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-37cee8f25ef5433ebff1a80e044b02722025-08-20T02:15:12ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-01912e11468610.1371/journal.pone.0114686Characterization of structure and function of ZS-9, a K+ selective ion trap.Fiona StavrosAlex YangAlejandro LeonMark NuttallHenrik S RasmussenHyperkalemia, 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.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0114686&type=printable |
| spellingShingle | Fiona Stavros Alex Yang Alejandro Leon Mark Nuttall Henrik S Rasmussen Characterization of structure and function of ZS-9, a K+ selective ion trap. PLoS ONE |
| title | Characterization of structure and function of ZS-9, a K+ selective ion trap. |
| title_full | Characterization of structure and function of ZS-9, a K+ selective ion trap. |
| title_fullStr | Characterization of structure and function of ZS-9, a K+ selective ion trap. |
| title_full_unstemmed | Characterization of structure and function of ZS-9, a K+ selective ion trap. |
| title_short | Characterization of structure and function of ZS-9, a K+ selective ion trap. |
| title_sort | characterization of structure and function of zs 9 a k selective ion trap |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0114686&type=printable |
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