Sodium zirconium cyclosilicate (ZS-9) is a crystalline inorganic cation exchange compound that possesses a remarkable ability to ensnab monovalent cations, particularly excess K+ and ammonium ions. The divalent ions Ca2+ and Mg2+ have exchange capacities for sodium zirconium cyclosilicate that are less than 0.05 mEq/g, and K+ has a selectivity that is more than 25 times greater than that of Ca2+ or Mg2+[1].

In the feces of Sprague-Dawley rats, sodium zirconium cyclosilicate (ZS-9; 2–6 g/kg; po; daily, for 5 d) is recovered and has an effective absorption and removal of potassium ions[2].

Animal/Disease Models: Sprague -Dawley rats[2]
Doses: 2, 4, and 6 g/kg
Route of Administration: Oral administration; daily, for 5 days
Experimental Results: Had 99% fecal recovery in rats. Uptake and removal of potassium ions in a dose-dependent manner.

Absorption, Distribution and Excretion
Sodium zirconium cyclosilicate is an inorganic, insoluble compound that is not readily metabolized by enzymes. Furthermore, studies have shown that it is not absorbed systemically. A rat body mass balance study indicated that sodium zirconium cyclosilicate is present in feces, with no evidence of systemic absorption. Sodium zirconium cyclosilicate is primarily excreted through feces.

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Metabolism / Metabolites
Sodium zirconium cyclosilicate is an inorganic, insoluble compound that is poorly metabolized by enzymes. Furthermore, studies have shown that it is not systemically absorbed. A rat in vivo mass balance study showed that sodium zirconium cyclosilicate was present in feces, with no evidence of systemic absorption. Due to these factors and its insolubility, no in vivo or in vitro studies have been conducted to date to investigate its effects on cytochrome P450 (CYP450) enzymes or transporter activities.

[1]. Characterization of structure and function of ZS-9, a K+ selective ion trap. PLoS One. 2014 Dec 22;9(12):e114686.

[2]. A phase 2 study on the treatment of hyperkalemia in patients with chronic kidney disease suggests that the selective potassium trap, ZS-9, is safe and efficient. Kidney Int. 2015 Aug;88(2):404-11.

Sodium Zirconium Cyclosilicate is an insoluble, non-absorbable sodium zirconium silicate formulated as an oral suspension powder, acting as a highly selective potassium ion scavenger. The drug is tasteless, odorless, and stable at room temperature when administered orally. Data from three double-blind, placebo-controlled trials and two open-label trials support its approval. Data show that the drug has an onset of action of approximately 1 hour, a median time to reach normal serum potassium levels of 2.2 hours, and 92% of patients achieved normal serum potassium levels within 48 hours of administration. The therapeutic effect can last up to 12 months. Sodium zirconium cyclosilicate is an insoluble, non-absorbable inorganic substance used as a potassium ion binder to treat hyperkalemia. After oral administration of the suspension, sodium zirconium cyclosilicate selectively targets and binds to potassium ions in the gastrointestinal tract, exchanging sodium ions for potassium ions. This increases potassium excretion in feces, reduces the concentration of free potassium in the gastrointestinal tract, and thus lowers serum potassium levels. It is used to treat hyperkalemia. See also: Zirconium cyclosilicate ions (with active moiety).

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Drug Indication
Sodium Zirconium Cyclosilicate is a potassium binder indicated for the treatment of hyperkalemia in adults.
FDA label

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Mechanism of Action
Sodium zirconium cyclosilicate (SZZC) is a condition characterized by elevated blood potassium levels, typically caused by cardiovascular, kidney, and metabolic disorders. Hyperkalemia occurs in 23% to 47% of patients with chronic kidney disease and/or chronic heart failure, and can lead to cardiac arrest and death. SZZC is a non-absorbable, non-polymeric inorganic powder with a uniform microporous structure that preferentially traps potassium ions, exchanging them for hydrogen and sodium ions. SZZC exhibits high selectivity for potassium ions, even in the presence of other cations such as calcium and magnesium ions, as confirmed by in vitro experiments. SZZC traps potassium ions throughout the gastrointestinal tract, reducing the concentration of free potassium in the gastrointestinal lumen, thereby lowering serum potassium levels and increasing fecal potassium excretion to alleviate hyperkalemia.

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Pharmacodynamics
Following administration of sodium zirconium cyclosilicate, serum potassium levels decrease as quickly as one hour, typically returning to normal within 24 to 48 hours. Sodium zirconium cyclosilicate does not affect serum calcium or magnesium concentrations or urinary sodium excretion. There is a strong correlation between initial serum potassium levels and therapeutic efficacy; patients with higher initial serum potassium levels experience a greater reduction in serum potassium. Due to the decrease in serum potassium concentration, urinary potassium excretion also decreases. A study in healthy subjects showed that daily administration of 5 or 10 grams of sodium zirconium cyclosilicate for four consecutive days resulted in a dose-dependent decrease in serum potassium concentration and total urinary potassium excretion, while fecal potassium excretion increased on average. No statistically significant changes in urinary sodium excretion were observed. Both in vitro and in vivo experiments have shown that sodium zirconium silicate can bind ammonium, thereby scavenging ammonium and increasing serum bicarbonate levels. In patients receiving sodium zirconium silicate, serum bicarbonate levels increased by 1.1 mmol/L with a once-daily dose of 5 g, 2.3 mmol/L with a once-daily dose of 10 g, and 2.6 mmol/L with a once-daily dose of 15 g, compared to a mean increase of 0.6 mmol/L in the placebo group. In the absence of other factors affecting renin and aldosterone, sodium zirconium silicate resulted in a mean decrease in serum aldosterone levels compared to the placebo group (14% increase), with the decrease being dose-independent (from -30% to -31%). No sustained effects of sodium zirconium silicate on systolic and diastolic blood pressure have been observed. Furthermore, compared to the placebo group (0.8 mg/dL) and the low-dose sodium zirconium silicate group (0.3 mg/dL), the mean blood urea nitrogen (BUN) was slightly increased in the three-times-daily doses of 5 g (-1.1 mg/dL) and 10 g (-2.0 mg/dL) groups.

H6O9SI3.2NA.ZR

371.50

363.769

17141-74-1

155804812

Typically exists as solid at room temperature

0

0

15

131

0

[O-][Si]1(O[Si](O[Si](O1)([O-])[O-])([O-])[O-])[O-].[Na+].[Na+].[Zr+4]

QMLIRKACNOVYNW-UHFFFAOYSA-N

InChI=1S/2Na.O9Si3.Zr/c;;1-10(2)7-11(3,4)9-12(5,6)8-10;/q2*+1;-6;+4

disodium;2,2,4,4,6,6-hexaoxido-1,3,5,2,4,6-trioxatrisilinane;zirconium(4+)

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)