2024 Volume 72 Issue 3 Pages 286-293
To explore drug interactions involving sodium zirconium cyclosilicate hydrate (SZC) and concomitant drugs like calcium antagonists (amlodipine and nifedipine) and β-blockers (carvedilol and bisoprolol), we investigate how these concomitant drugs influenced the administration of SZC in an artificial intestinal juice. Initially, we assessed the potassium ion adsorption capacity, ranking it as follows: calcium polystyrene sulfonate (CPS, 54.9 mg/g) < sodium polystyrene sulfonate (SPS, 62.1 mg/g) < SZC (90.8 mg/g). However, the adsorption equilibrium was achieved in the order of CPS ≒ SPS (within 1 min) < SZC (within 1 h). Subsequently, we determined the residual percentages of amlodipine, nifedipine, carvedilol, and bisoprolol, finding them to be 79.0–91.9% for SZC, 0.38–38.4% for SPS, and 0.57–29.0% for CPS. These results suggest the efficacy of SZC in managing hyperkalemia alongside concomitant drugs in an artificial intestinal juice, with particular emphasis on amlodipine (calcium antagonist) and carvedilol (β-blocker). Additionally, we identified the presence of carbon, nitrogen, and oxygen components from both drugs on the SZC surface following interaction. We also evaluated how amlodipine, nifedipine, carvedilol, and bisoprolol affected the administration of SZC in the presence of potassium ions. Our results indicate that potassium ions and concomitant drugs did not interfere with each other in the artificial intestinal juice. These results offer valuable insights into the administration of SZC in conjunction with concomitant drugs. Lastly, the presented data shows qualitative results in this study.
Hyperkalemia, a common electrolyte disorder, is associated with an increased risk of cardiac arrhythmias and mortality.1) Lemoine et al. have previously reported this association with fatal cardiac dysrhythmias.2,3) Patients with chronic kidney disease (CKD), heart failure, and diabetes, especially those receiving renin-angiotensin-aldosterone system inhibitors, are at an increased risk of developing hyperkalemia.4–6) Potassium regulation involves two concurrent processes: the internal system controls the total body potassium within both intracellular and extracellular compartments, while the external system manages the balance and distribution of potassium.7) Approximately 98% of potassium is typically found intracellularly, with only 2% in the extracellular space.8–10) Therefore, maintaining strict control of intracellular potassium levels is crucial for hyperkalemia treatment.
Previous studies have discussed the pharmacological treatment and pathogenesis of acute and chronic hyperkalemia in CKD patients.11,12) Specifically, treatments like calcium gluconate administration, glucose-insulin therapy, and blood purification therapy are beneficial for severe or acute hyperkalemia. Conversely, cation-exchange resins such as sodium polystyrene sulfonate (SPS), calcium polystyrene sulfonate (CPS), and sodium zirconium cyclosilicate hydrate (SZC) are effective for managing mild or chronic hyperkalemia. These agents function by exchanging cations (sodium or calcium ions) with potassium ions in the gastrointestinal tract2,3) (Fig. 1).
SPS received U.S. Food and Drug Administration (FDA) approval back in 1985, but its use has been supported by limited reports.2) In 2017, the FDA reported interactions between SPS and several oral concomitant drugs, including amlodipine besylate, metoprolol, amoxicillin, furosemide, warfarin, and phenytoin. These interactions could potentially reduce the effectiveness of these drugs due to the interactions with SPS. Therefore, the FDA recommended that concomitant drugs should be taken at least 3 h before or after SPS administration.13) Furthermore, in our previous study, we found that calcium antagonists (amlodipine and nifedipine) and β-blocker drugs (carvedilol and bisoprolol) readily interacted with SPS in an artificial intestinal juice.14) In contrast, SZC has received approval for the treatment of hyperkalemia in adults in the EU,15) the U.S.A.,16) and Canada,17) and most recently, Japan in 2020. Unlike SPS and CPS, SZC is a more selective and efficient monovalent cation exchanger, specifically capturing potassium ions and ammonium ions in the intestinal tract.18,19) Moreover, SZC administration reduces the risk of constipation associated with potassium binders because it does not absorb water. SZC is an attractive therapeutic agent as it is typically administered as a once-daily dose, unlike SPS and CPS. However, it is important to note that the SZC package insert in Japan advises caution when co-administering it with four types of drugs: anti-human immunodeficiency virus (HIV) drugs, azole antifungals, tyrosine kinase inhibitors, and tacrolimus.20) Despite its widespread use, there is a limited number of studies that have evaluated the efficacy and safety of SZC in terms of drug interactions with concomitant drugs.
Therefore, we conducted in-vitro assessments to examine the interactions between SZC and concomitant drugs commonly used. Additionally, we investigated how potassium ions influenced these drug interactions in an artificial intestinal juice.
SPS (Kayexalate® Powder), CPS (Kalimate® Powder), and SZC (Lokelma® 5 g Powder for suspension (single-dose package)) were purchased from Torii Pharmaceutical Co., Ltd. (Tokyo, Japan, Lot No.: KGG511, KFJ513, KEI512), Kowa Co., Ltd. (Aichi, Japan, Lot No.: FB2A), and AstraZeneca K.K. (Osaka, Japan, Lot No.: NH2759A, NC3797A), respectively (Fig. 1). Additionally, we obtained potassium chloride (special grade) from FUJIFILM Wako Pure Chemical Corporation Corp. (Osaka, Japan). For our experiments, we prepared artificial intestinal juice (the second fluid, pH 6.8) following a previously reported method (The Japanese Pharmacopoeia 18th Edition, JP XVIII).21) The concomitant drugs used in this study are listed in Table 1.
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Moreover, we assessed the characteristics of SZC through various analytical techniques, including X-ray diffraction (XRD) pattern analysis, thermogravimetric-differential thermal analysis (TG-DTA), and scanning electron microscopy (SEM). MiniFlex II (Rigaku Corp., Tokyo, Japan) was used to measure the crystal phase (measurement condition, radiation source, CuKα; tube voltage, 30 keV; and tube current, 15 mA). TG-DTA was carried out using a TG8210 (Rigaku Corp.) in an air atmosphere, with a target temperature of 1000 °C and a heating time of 10 °C/min. Surface morphology was examined using a SU1510 (Hitachi High-Technologies Corp., Tokyo, Japan) with an accelerating voltage of 15.0 keV and a beam diameter of 5 µm.
Adsorption Capacity of Potassium Ions Using Adsorbents in Artificial Intestinal JuiceTo begin, we quantified the adsorption of potassium ions by various adsorbents. The concentration of potassium ions was determined with reference to both “The National Health and Nutrition Survey in Japan, 2016” and the “Guideline: Potassium intake for adults and children.”22,23) In this study, each adsorbent (SZC, 5.0 g; SPS, 2.5 g; and CPS, 5.0 g) was mixed with 500 mL of artificial intestinal juice containing 2000 mg/L of potassium ions. This mixture was agitated at 100 rpm and maintained at 37 °C for 30 s; 1, 10, 30, and 60 min; and 2 and 4 h. Following filtration using a 0.45-µm membrane filter, the concentration of potassium ions was determined using an inductively coupled plasma optical emission spectrometer (ICP-OES, iCAP 7600 Duo, Thermo Fisher Scientific Inc., MA, U.S.A.). The amount of adsorbed potassium ions was calculated by comparing the levels before and after adsorption. Additionally, with SZC, the concentration of potassium ions was changed from 1000 mg/L to 4000 mg/L. The data are presented as the mean ± standard error (n = 2). We evaluated a study at the minimum dosage levels of SZC (5.0 g), SPS (2.5 g), and CPS (5.0 g) that are likely to be taken actual patients in this experiment.
Adsorption Capacity of Concomitant Drugs Using Adsorbents in Artificial Intestinal JuiceThe concomitant drugs (shown in Table 1) were mixed with 500 mL of artificial intestinal juice containing no more than 2% methanol (v/v).24) The initial concentrations of solubilized amlodipine besylate, nifedipine, carvedilol, and bisoprolol fumarate were set at 10, 40, 20, and 10 mg/L, respectively, based on the package inserts provided with each drug in Japan. Subsequently, each adsorbent (SZC, 5.0 g; SPS, 2.5 g; and CPS, 5.0 g) was mixed with the prepared sample solution and stirred at 100 rpm at 37 °C for 30 s; 1, 10, 30, and 60 min and 2 and 4 h. After filtration using a 0.45-µm membrane filter, the concentrations of concomitant drugs were determined using HPLC (LC-10ATVO (pump), CTO-10ASVP (column oven), and SPD-10AVP (UV-Vis detector), Shimadzu Corp., Kyoto, Japan) under specific measurement conditions as detailed in Table 2. These conditions included a flow rate of 1.0 mL/min, an injection volume of 1.0 µL, and a detection temperature of 37 °C in our experimental setup. Calibration curves for concomitant drugs had already been established under these conditions, as depicted in Fig. 2. Finally, the adsorbent (SZC) after adsorption treatment was collected and then dried at 50 °C for 24 h. Subsequently, the collected SZC adsorbent was coated with platinum using an automatic magnetron sputter (MSP-20-UM, Vacuum Device Inc., Ibaraki, Japan). After that, electron probe micro analyzer (EPMA, JXA-8530F, JEOL Ltd., Tokyo, Japan) with an accelerating voltage of 15.0 keV and a beam diameter of 2 µm was employed to record the elemental analysis of the SZC surface before and after adsorption. The data are presented as the mean ± standard error (n = 2).
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Range of concentration: 0.25–10 mg/L (Amlodipine besylate and Bisoprolol fumarate), 0.5–20 mg/L (Carvedilol), 1–40 mg/L (Nifedipine).
We conducted experiments to examine how SZC adsorbs concomitant drugs and potassium ions in an artificial intestinal juice. Initially, we prepared a potassium ion solution with a concentration of 2000 mg/L in the artificial intestinal juice. Next, we mixed concomitant drugs (amlodipine, 20 mg/L; nifedipine, 40 mg/L; carvedilol, 20 mg/L; or bisoprolol, 10 mg/L) with 500 mL of the prepared sample solution. The mixture was stirred at 100 rpm at 37 °C for 30 s; 1, 10, 30, and 60 min; and 2 and 4 h. Subsequently, we used a 0.45-µm membrane filter for filtration and measured the concentrations of concomitant drugs and potassium ions using the methods above. The data are presented as the mean ± standard error (n = 2).
In 2020, SZC received approval in Japan for treating hyperkalemia due to its cation-exchange capabilities. It possesses a uniform microporous structure and is an inorganic crystal devoid of polymers. SZC functions by facilitating ion exchange, allowing for the substitution of potassium ions with sodium or hydrogen ions to rectify hyperkalemia. Nevertheless, some fundamental characteristics of SZC remained unclear. Figure 3 illustrates the XRD patterns, TG-DTA, and SEM images of SZC. The XRD pattern and SEM image show the morphological properties of the adsorbent. In the XRD patterns, numerous sharp peaks were observed, indicating that SZC exhibited a crystalline structure. Additionally, the SEM image revealed the presence of various particles at different sizes. Changes in mass and/or thermal reactions with calcination were evaluated through TG-DTA analysis. The TG-DTA curves indicated that water adhered to the surface of SZC was dehydrated at approximately 200 °C, comprising octahedrally and tetrahedrally oxygen-coordinated zirconium and silicon atoms. Finally, the weight loss percentage was approximately 15% after calcination at 1000 °C. The average pore size is approximately 3 Å, making it highly compatible with potassium ions and ammonium ions (which have positive charges and ionic radii of 1.43 and 1.33 Å).25) Previous research has reported that SZC exhibits over 25 times the selectivity for potassium ions compared to calcium ions or magnesium ions. Consequently, the total potassium-binding capacity of SZC is estimated to be around ten times higher than that of SPS.19)
The adsorption capacity of potassium ions by SZC, SPS, and CPS was evaluated, as depicted in Fig. 4. Under our experimental conditions, SPS and CPS exhibited a faster adsorption rate than SZC (Fig. 4(A)). The point of adsorption equilibrium was reached within 1 h for SZC, 1 min for SPS, and 1 min for CPS. After a 4 h experiment, the quantities of potassium ions adsorbed were 90.8 mg/g for SZC, 62.1 mg/g for SPS, and 54.9 mg/g for CPS. These findings indicate that SZC administration is a valuable treatment for reducing potassium ion concentrations in artificial intestinal juice when compared to SPS and CPS. Subsequently, we demonstrated the adsorption of potassium ions onto SZC in the artificial intestinal juice at different concentrations (Fig. 4(B)). The amount adsorbed increased with higher initial potassium ion concentrations (1000 < 2000 < 4000 mg/L). According to the JP XVIII, the potassium ion exchange capacity was defined as 110–135 mg/g for SPS and 53–71 mg/g for CPS, respectively. In conclusion, the order of potassium ion adsorption capacity in the artificial intestinal juice was as follows: SZC > SPS > CPS. Therefore, our subsequent experiments primarily focused on SZC.
(A) Adsorbents: SZC (5.0 g), SPS (2.5 g) or CPS (5.0 g), initial concentration of 2000 mg/L. (B) Adsorbent: SZC (5.0 g), initial concentration: 1000–4000 mg/L. Solvent volume: 500 mL, elapsed time: 30 s, 1, 10, 30, 60 min, 2, 4 h, temperature: 37 °C, agitation speed: 100 rpm, the data are presented as the mean ± standard error (n = 2).
In this section, we conducted experiments to explore the drug interactions between SZC and concomitant drugs listed in Table 2. Figure 5 illustrates the adsorption capacity of these concomitant drugs, including amlodipine, nifedipine, carvedilol, and bisoprolol, using SZC, SPS, and CPS. As shown in Fig. 5, the residual rates of amlodipine, nifedipine, carvedilol, and bisoprolol were 79.0–91.9% for SZC, 0.38–38.4% for SPS, and 0.57–29.0% for CPS. These results suggest that SZC had limited capacity to adsorb these drugs in our experimental setup.
●: SZC, □: SPS, ▲: CPS Initial concentration: 10 mg/L (Amlodipine and Bisoprolol), 40 mg/L (Nifedipine), 20 mg/L (Carvedilol), solvent volume: 500 mL, adsorbents: 5.0 g (SZC and CPS), 2.5 g (SPS), elapsed time: 30 s, 1, 10, 30, 60 min, 2, 4 h, temperature: 37 °C, agitation speed: 100 rpm, the data are presented as the mean ± standard error (n = 2).
Ohta et al. previously reported that the adsorption of non-ionic drugs and cationic or anionic drugs in the presence of SPS (CPS) in artificial intestinal juice was significantly influenced by ionic and/or hydrophobic interactions.24) In our study, amlodipine (pKa: 9.3), carvedilol (pKa: 8.0), and bisoprolol (pKa: 9.6) are cationic drugs in the artificial intestinal juice (pH 6.8) while nifedipine (pKa: over 13) is a non-ionic drug in the artificial intestinal juice. Therefore, these four drugs readily reacted with SPS (or CPS) due to ionic and/or hydrophobic interactions. In contrast, SZC features an asymmetrical seven-membered ring as the framework for its pore openings, with an average width of approximately 3 Å.7) The size of the concomitant drugs used in our study exceeded 3 Å, making it difficult for SZC to interact with these drugs in the artificial intestinal juice. Therefore, when patients concurrently receive cation-exchange resins and concomitant drugs, SZC proves to be a valuable agent for hyperkalemia treatment compared to SPS and CPS.
Additionally, we directed our attention to amlodipine (calcium antagonist) and carvedilol (β-blocker drug) to elucidate the interaction mechanism. First, SEM images of SZC were compared before and after the adsorption of amlodipine or carvedilol (Fig. 6). Notably, no significant alterations in SZC morphology were observed before and after the interaction, suggesting that the crystal phase of SZC remained intact following the interaction. Next, we conducted a qualitative analysis of the SZC surface before and after interaction, as depicted in Fig. 7. As shown in Fig. 7, the intensities of components from the concomitant drugs (carbon (C), nitrogen (N), or oxygen (O)) were higher after the interaction compared to before the interaction under our experimental conditions (with intensities ranging from 2.20 to 5.40 times higher for amlodipine and 1.47 to 5.20 times higher for carvedilol, respectively). This suggests that amlodipine and carvedilol may have been captured on the surface of SZC. Further studies are required to provide a detailed understanding of the drug interactions between SZC and concomitant drugs.
The SZC adsorbent after adsorption treatment was collected and then dried at 50 °C for 24 h. The collected SZC adsorbent was coated with platinum using an automatic magnetron sputter. Measurement conditions: accelerating voltage of 15.0 keV and a beam diameter of 2 µm.
In medical practice, adsorbents like SZC, SPS, and CPS are often administrated alongside other prescription drugs to patients with CKD. Therefore, our primary focus was on SZC, and we proceeded to evaluate the potential drug interactions between SZC and concomitant drugs in an artificial intestinal juice setting. Concomitant drugs, specifically amlodipine, nifedipine, carvedilol, and bisoprolol, were chosen. The amount of concomitant drugs adsorbed when using SZC is presented in Fig. 8. Importantly, the presence of potassium ions at a concentration of 2000 mg/L did not influence the adsorption capacity of these concomitant drugs under our experimental conditions. It is worth noting that a prior study had reported significant effects potassium ions on the adsorption capacity of carvedilol and/or bisoprolol when using SPS.14) Additionally, the amount of potassium ions adsorbed by SZC remained unaffected by amlodipine, nifedipine, carvedilol, and bisoprolol (Fig. 9). Although some studies have explored treatments for hyperkalemia in CKD patients, there is a scarcity of research on the drug interactions between SZC and concomitant drugs in an artificial intestinal juice.8,26,27) As demonstrated by our results, this information proves valuable for the administration of SZC in the presence of concomitant drugs. Furthermore, SZC holds promise as a potentially safe and effective therapeutic agent for managing hyperkalemia in CKD patients who are currently taking other medications.
○: without potassium ions, ●: with potassium ions. Initial concentration: 2000 mg/L (potassium ions), 20 mg/L (Amlodipine and Carvedilol), 40 mg/L (Nifedipine), 10 mg/L (Bisoprolol), solvent volume: 500 mL, adsorbent: 5.0 g (SZC), elapsed time: 30 s, 1, 10, 30, 60 min, 2, 4 h, temperature: 37 °C, agitation speed: 100 rpm, the data are presented as the mean ± standard error (n = 2).
□: without drug, ■: with drug. Initial concentration: 2000 mg/L (potassium ions), 20 mg/L (Amlodipine and Carvedilol), 40 mg/L (Nifedipine), 10 mg/L (Bisoprolol), solvent volume: 500 mL, adsorbent: 5.0 g (SZC), elapsed time: 30 s, 1, 10, 30, 60 min, 2, 4 h, temperature: 37 °C, agitation speed: 100 rpm, the data are presented as the mean ± standard error (n = 2).
We conducted a comprehensive assessment of the interactions between SZC and concomitant drugs, including calcium antagonists and β-blocker drugs, within an artificial intestinal juice environment. Notably, SZC exhibited a higher adsorption capacity for potassium ions compared to SPS and CPS. Furthermore, the quantity of potassium ions adsorbed by SZC increased with higher initial concentrations of potassium ions (1000 < 2000 < 4000 mg/L). Additionally, when examining the residual rates of amlodipine, nifedipine, carvedilol, or bisoprolol in the artificial intestinal juice, we found that SZC retained 79.0–91.9% of these drugs, while SPS retained 0.38–38.4%, and CPS retained 0.57–29.0%. These findings underscore the usefulness of SZC as a treatment for hyperkalemia in the presence of concomitant drugs, outperforming SPS and CPS in this regard. Moreover, we verified the presence of amlodipine and/or carvedilol on the surface of SZC following their interaction under our specific experimental conditions. Our experiments revealed that potassium ions and concomitant drugs did not mutually affect each other within the artificial intestinal juice. Hence, SZC was found to be a promising adsorbent for more effectively and/or safety treatment of hyperkalemia compared to other classical adsorbents. Lastly, the presented data shows qualitative results in this study.
The authors declare no conflict of interest.
