Fundamental Investigation of Adsorption Behavior onto Sodium Polystyrene Sulfonate to Potassium Ions and Its Concomitant Drugs in the Digestive Tract

Abstract

To verify the interaction between sodium polystyrene sulfonate (SPS) and its concomitant drugs, we elucidated the capability of potassium ions and concomitant drugs to adsorb onto SPS and the effect of their coexistence on the amount adsorbed. We identified 14 drugs used concomitantly with SPS from 2017–2019 in our investigation, and 5 drug preparations used in the clinical setting were used for the experiments. In the artificial intestinal juice, SPS adsorbed 39.05–69.77 mEq/g of potassium ions. Amlodipine besylate and nifedipine were well-adsorbed, while azosemide and febuxostat were did not adsorb well onto SPS. Our results and the results of a previous study suggest that additives in drug preparations affect the adsorption of drugs onto SPS. The adsorption kinetics onto SPS of drugs conformed to the pseudo-second order model. However, the adsorption of amlodipine besylate completely may not be fitted to the pseudo-second order model. The amount of amlodipine besylate adsorbed under the coexistence of potassium ions decreased compared to when potassium ions were absent. The amount of nifedipine and potassium ions adsorbed remained constant, regardless of whether potassium ions were present or not. These results might be due to the differences in their mechanisms of adsorption onto SPS and to the characteristics of the drugs. In a clinical setting, SPS is used concomitantly with various oral drugs. The interaction between SPS and its other concomitant drugs need to be elucidated more to obtain enough evidence for pharmacists to propose the appropriate prescription.

Introduction

Chronic kidney disease (CKD) is a disease concept first defined by National Kidney Foundation (NKF) in 2002 and classified the severity by Kidney Disease Improving Global Outcomes (KDIGO).¹⁾ Various complications, including hypertension, anemia, and electrolyte abnormalities, have been observed to arise in CKD patients.²⁾ Particularly, hyperkalemia is well-known as one of the most severe complications of CKD.³⁾ Hyperkalemia is caused not only by the decrease in potassium excretion from the renal tubules, but also by the use of therapeutic medicines for CKD called renin-angiotensin-aldosterone system inhibitors (RAAS-Is), such as angiotensin converting enzyme inhibitors (ACE-Is) and angiotensin II receptor blockers.⁴⁾ The progression of hyperkalemia may induce arrhythmia, and, in serious cases, may lead to death. Moreover, high serum potassium levels increase the overall mortality rate of CKD patients.⁵⁾ Therefore, in CKD patients, it is crucial that serum potassium levels are improved from an early stage.

In the clinical setting, cation-exchange resins, namely sodium polystyrene sulfonate (SPS) and calcium polystyrene sulfonate (CPS), have been long used for hyperkalemia.⁶⁾ SPS and CPS exchange sodium and calcium ions for the potassium ions in the digestive tract. Yu et al. indicated that low-dose SPS and CPS treatment can control chronic and mild hyperkalemia effectively in the long-term.⁷⁾ Chernin et al. reported that low-dose SPS was effective as secondary prevention for hyperkalemia induced by RAAS-Is in CKD patients with heart disease.⁸⁾ However, these resins have the potential to bind to other metal ions and concomitant drugs, in addition to potassium ions. In 2017, the U.S. Food and Drug Administration (FDA) reported that based on an in-vitro study, SPS may bind to other oral drugs, including amlodipine besylate, metoprolol, amoxicillin, furosemide, warfarin, and phenytoin. Furthermore, the FDA recommended separating the administration of SPS from concomitant drugs by at least 3 h.⁹⁾ In several regions, this recommendation has already been reflected in the drug information of SPS preparation. However, there are few reports that evaluated about the binding potential of SPS to its concomitant drugs in the digestive tract. Ohta et al. reported that, in an in-vitro study, CPS showed adsorption capabilities to several concomitant drugs.¹⁰⁾ Toyoguchi et al. also showed that CPS adsorbed antidepressants, such as clomipramine, imipramine, mianserine, and trazodone, and antimicrobial agents, such as ciprofloxacin in-vitro.¹¹⁾

Clarification of the adsorption behavior of SPS to concomitant drugs may provide useful information for the prescription of therapeutic medicines to hyperkalemia patients with CKD. We had reported the drugs used well concomitantly with SPS and the effect of concomitant drugs on the efficacy of SPS.¹²⁾ As a new attempt, we evaluated not only the adsorption capability of SPS to concomitant drugs obtained from the prior research in the digestive tract, but also the effect of potassium ions coexistence on the drug absorption of SPS in the present study.

Experimental

Investigation of Concomitant Drugs of SPS

To investigate what drugs are used concomitantly with SPS, we selected 186 patients who received SPS treatment for the first time in the Kindai University Hospital in Osaka from 2017 to 2019. Table 1 shows the list of drugs used concomitantly with SPS obtained from the medical records. We obtained the data with approval from the Ethics Committee of the Kindai University Faculty of Pharmacy and Faculty of Medicine (Approval ID: 21-180 and R02-211).

Table 1. Concomitant Drugs of SPS¹²⁾

Drugs	n (%)a)
Febuxostat	61 (33)
Azosemide	39 (21)
Amlodipine besylate	38 (20)
Lansoprazole	34 (18)
Magnesium oxide	34 (18)
Furosemide	31 (17)
Sodium hydrogen carbonate	31 (17)
Nifedipine	30 (16)
Carvedilol	28 (15)
Aspirin	27 (15)
Atorvastatin calcium	25 (13)
Azilsartan	22 (12)
Bisoprolol fumarate	22 (12)
Imidapril	19 (10)

a) A total of 186 patients were included in this investigation.

Materials

SPS (Kayexalate^® powder) was obtained from Torii Pharmaceutical Co., Ltd. (Tokyo, Japan; Lot No.: KFJ513 and KGG511). Potassium chloride (guaranteed reagent) was obtained from FUJIFILM Wako Pure Chemical Corporation (Osaka, Japan). The concomitant drugs used in this study are shown in Table 2. The artificial intestinal juice was prepared with reference to the recipe of the second fluid (pH 6.8) for the disintegration test in The Japanese Pharmacopoeia 18th Edition (JP XVIII).¹³⁾ Briefly, 250 mL of 0.2 M sodium dihydrogen phosphate solution and 118 mL of 0.2 M sodium hydroxide solution were mixed, and up to 1-L distilled water was added.

Table 2. List of Concomitant Drugs of SPS Used in This Study

Generic names	Trend names	Marketing authorization holder	Lot No.
Amlodipine besylate	Norvasc® OD tablet 5 mg	Pfizer Japan Inc. (Tokyo, Japan)	EK9672
Febuxostat	Feburic® tablet 10 mg	Teijin Pharma Ltd. (Tokyo, Japan)	00011
Nifedipine	Adalat® CR tablet 10 mg	Bayer Yakuhin, Ltd. (Osaka, Japan)	JPS5517
Furosemide	Furosemide tablet 10 mg “TAKEDA TEVA”	Teva Takeda Pharma Ltd. (Aichi, Japan)	FS1567
Azosemide	Diart® tablet 10 mg	Sanwa Kagaku Kenkyusho Co., Ltd. (Aichi, Japan)	FVO1201

The elemental analysis of SPS surface was measured using an electron probe micro analyzer (EPMA; JXA-8530F, JEOL Ltd., Tokyo, Japan) with an accelerating voltage of 15.0 keV and a beam diameter of 5 µm. The binding energy of SPS was measured using an electron spectroscopy for chemical analysis (ESCA; AXIS-NOVA, Shimadzu Co., Kyoto, Japan) with AlKα, a voltage of 15.0 keV, and a current of 10 mA. The concentration of the potassium ions was measured through inductively coupled plasma optical emission spectrometer (ICP-OES; iCAP 7600 Duo, Thermo Fisher Scientific K.K., Tokyo, Japan). The maximum absorption wavelengths of the drugs were determined using UV-visible absorption spectroscopy (UV-Vis; UV-1280, Shimadzu Co.). Quantitative analysis of the concomitant drugs was performed by UV-Vis and HPLC (LC-10ATVP (pump), CTO-10ASVP (column oven), SPD-10AVP (UV-Vis detector), Shimadzu Co.) using two conditions:

System A: Mobile phase: 13 : 7 methanol and potassium dihydrogen phosphate; column: stainless-steel column 4.6 mm in diameter and 15 cm in length, packed with octadecylsilanized silicagel for LC (5 µm in particle diameter, COSMOSIL^® 5C18-AR-II Packed Column 4.6 mmI.D., × 150 mm, Nacalai Tesque Inc., Kyoto, Japan.); injection: 10 µL; flow rate: 1.0 mL/min; temperature: 37 °C.

System B: Mobile phase: 11 : 9 methanol and diluted 0.05 mol/L disodium hydrogen phosphate solution adjusted to pH 6.1 with phosphoric acid; column: stainless-steel column 4.6 mm in diameter and 15 cm in length, packed with octadecylsilanized silicagel for LC (5 µm in particle diameter, COSMOSIL^® 5C8-MS Packed Column 4.6 mm I.D., × 150 mm, Nacalai Tesque Inc.); injection: 10 µL; flow rate: 1.0 mL/min; temperature: 37 °C.

Adsorption Capability of Potassium Ions onto SPS at Different Initial Concentrations in the Artificial Intestinal Juice

SPS binds to potassium ions in the digestive tract. This reaction is occurred both fasting and non-fasting states. That is, potassium ions adsorbed onto SPS are not depended on the meals. In general, the potassium ion concentration of intestinal fluid is about 11 mEq/L (430 mg/L). On the other hand, we intake about 77 mEq (3010.7 mg) of potassium ion from meals.¹⁴⁾ Many SPS is administered after meals. Therefore, in the present study, the initial concentrations of potassium ion were determined 1000–4000 mg/L in the artificial intestinal juice.

SPS (2.5 g) was added in each concentration of the potassium test solution. Then, the reaction mixtures were stirred at 100 rpm, 37 °C for 30, 60, and 90 min, and for 2, 3, 4, 5, and 6 h. After stirring, each solution was filtered using a 0.45 µm membrane filter and the potassium ion concentration of the solution was measured using ICP-OES. The amount of potassium adsorbed was calculated using Eq. (1):

  

(1)

where q is the amount adsorbed (mg/g), C₀ and C_e are the initial and the equilibrium concentrations (mg/L), respectively, V is the volume of the test solution (L), and W is the weight of the adsorbents (g). The data are expressed as the mean ± standard error (S.E.).

Adsorption Study of the Concomitant Drugs onto SPS in the Artificial Intestinal Juice

All adsorption experiments were carried out with reference to previous studies.^10,11,15) Tablets of the drugs shown in Table 2 were pulverized using a mortar and pestle. Further, an amount of powder equivalent to one dose was dissolved in 500 mL of the artificial intestinal juice. SPS (2.5 g) was added to the test solution. The reaction mixtures were stirred at 100 rpm, 37 °C for 10, 20, and 30 s, for 1, 3, 5, 10, 30, 60, and 90 min, and for 2, 3, 4, 5, and 6 h. After stirring, each solution was filtered using a 0.45 µm membrane filter. The concentration of each drug was measured using UV-Vis and HPLC. The amount of drug adsorbed were calculated using Eq. (1) and the residual rates of the drugs in the test solution after adsorption onto SPS were calculated using Eq. (2):

  

(2)

where R_d is the residual rate of the concomitant drugs after adsorption onto SPS (%) and C_e and C₀ are the equilibrium and the initial concentrations (mg/g), respectively. The data were expressed as the mean ± S.E.

Adsorption Behavior of SPS under the Coexistence of Potassium Ions and Concomitant Drugs in the Artificial Intestinal Juice

One dose of pulverized amlodipine besylate or nifedipine and 1000–4000 mg/L of potassium ions were dissolved in the artificial intestinal juice. SPS (2.5 g) was added to the test solution. The reaction mixture was stirred at 100 rpm, 37 °C for 10, 20, and 30 s and for 1, 3, 5, and 10 min. The mixture with nifedipine was stirred for 30 s, for 1, 10, 30, and 60 min, and for 2 and 4 h in the same conditions. After stirring, the solution was filtered with a 0.45 µm membrane filter. The concentrations of the potassium ions and each drug were measured using ICP-OES and HPLC, respectively. The amount of potassium ions and the adsorption and the residual rates of each drug were calculated using Eq. (1) and (2), respectively. The data are expressed as the mean ± S.E.

Results

Adsorption Capability of Potassium Ions onto SPS at Different Initial Concentrations in the Artificial Intestinal Juice

Figure 1 shows the amount of potassium ions adsorbed onto SPS in the artificial intestinal juice. Results showed that the saturation of potassium ion adsorption was reached after an hour and that the amount of potassium ions adsorbed increased as the initial concentration increased. In JP XVIII, the potassium exchange capacity of SPS was defined at 110–135 mg/g (2.81–3.45 mEq/g).¹³⁾ In this study, the amount of potassium ions adsorbed 6 h after stirring began was 39.1–69.8 mg/g (1.00–1.79 mEq/g). The data obtained from our investigation was a little different from that in JP XVIII. We believe that this difference was probably due to the difference in experimental conditions. Therefore, it was elucidated that SPS has a potential for potassium ion adsorption in artificial intestinal juice.

Fig. 1. Amount of Potassium Ion Adsorption onto SPS at Different Concentration

Initial concentration: 1000–4000 mg/L, volume: 500 mL, adsorbent: 2.5 g, elapsed time: 30, 60, 90 min, 2, 3, 4, 5, 6 h, temperature: 37 °C, agitation speed: 100 rpm.

The electron probe micro analyzer and the electron spectroscopy for chemical analysis were used to characterize the interaction between the potassium and the SPS surface. Figure 2 shows the surface analyzes of SPS before and after potassium ion adsorption. From results of qualitative analysis, each intensity of potassium was 7 (before adsorption), 46 (K 1000 mg/L), 62 (K 2000 mg/L) and 81 (K 4000 mg/L). That is, the increase in the signal of potassium on the SPS surface after adsorption, was confirmed with an increase in the initial concentration of potassium ions. According to the database of binding energy of ESCA published by the National Institute of Standards and Technology (NIST), peaks of potassium are detected at around 19, 35, 294, 297, 380 eV. In the present result of binding energy on the SPS surface, the increment of peaks at around 290 and 375 eV was confirmed after potassium adsorption.

Fig. 2. Surface Analyzes of SPS Surface before and after Potassium Ion Adsorption

UV-Vis Spectrums of the Concomitant Drugs of SPS

The UV-Vis spectrums of amlodipine besylate, nifedipine, furosemide, azosemide, and febuxostat are shown in Fig. 3 (hereinafter, all data regarding amlodipine besylate show as the ones of only amlodipine). Based on the results, we determined the measurement wavelengths of each concomitant drug as follows: 364.0 nm for amlodipine besylate, 237.3 nm for nifedipine, 277.5 nm for furosemide, 282.7 nm for azosemide, and 314.0 nm for febuxostat. Moreover, the calibration curves of each drug indicated strong correlations (each correlation coefficient: r = 1.000). It was 0.5–10 mg/L for amlodipine besylate, 1–40 mg/L for nifedipine, and 0.1–20 mg/L for furosemide, azosemide, and febuxostat (Fig. 4).

Fig. 3. UV-Vis Spectrums of Drugs Used Concomitantly with SPS

Concentration: 10 mg/L (amlodipine besylate), 40 mg/L (nifedipine), 20 mg/L (furosemide, azosemide, febuxostat).

Fig. 4. Correlation Coefficients of Drugs Used Concomitantly with SPS

Range of concentration: 0.5–10 mg/L (amlodipine besylate), 1–40 mg/L (nifedipine), 0.1–20 mg/L (furosemide, azosemide, febuxostat).

Adsorption Study of the Concomitant Drugs onto SPS in the Artificial Intestinal Juice

Figure 5 shows the residual rates of the concomitant drugs after adsorption by SPS in the artificial intestinal juice. The residual rates of each drug 6 h after stirring began were 3.6% for amlodipine besylate, 36.2% for nifedipine, 100.6% for furosemide, 95.9% for azosemide, and 94.5% for febuxostat. Furosemide was not adsorbed by SPS at all, while very little azosemide and febuxostat were adsorbed by SPS. Amlodipine besylate adsorption saturated in less than a minute, while nifedipine adsorption reached saturation at approximately 2 h after stirring began.

Fig. 5. Adsorption of Concomitant Drugs onto SPS in the Artificial Intestinal Juice

Initial concentration: 10 mg/L (amlodipine besylate), 40 mg/L (nifedipine), 20 mg/L (furosemide, azosemide, febuxostat), solution volume: 500 mL, adsorbent: 2.5 g, elapsed time: 10, 20, 30 s, and 1, 3, 5, 10, 30, 60, 90 min, and 2, 3, 4, 5, 6 h, temperature: 37 °C, agitation speed: 100 rpm.

Data obtained from Fig. 5 was fitted to the adsorption kinetics models in aqueous phase, the pseudo-first order model and the pseudo-second order model. The pseudo-first order and pseudo-second order models were proposed by Lagergren in 1898 and Ho and McKay in 1999.^16,17) The linear formulas of each model are in Eqs. (3) and (4):

  

(3)

  

(4)

where q_e and q_t are the amounts adsorbed at equilibrium and at any time t (mg/g), respectively; k₁ (1/h) and k₂ (g/mg/h) are the kinetic constants of the pseudo-first order model and the pseudo-second order model, respectively. Figure 6 shows the fitting results of the adsorption data in each model. The adsorption rate of furosemide could not be calculated because it was not adsorbed by SPS at all. As seen in the figure, the correlation coefficients of the pseudo-second order models were higher than those of the pseudo-first order models in every drug. Therefore, we elucidated that drug adsorption using SPS mainly occurred based on the pseudo-second order kinetics model. However, in amlodipine besylate, the intercept of linear of the pseudo-second order model showed a negative value. Therefore, the adsorption of amlodipine besylate onto SPS completely may not be fitted to this pseudo-second order model even if the correlation coefficient is 1.000.

Fig. 6. Fitting Results of Adsorption Kinetics of SPS to Pseudo-First Order Model and Pseudo-Second Order Model

Adsorption Study of Potassium Ions and Concomitant Drugs onto SPS in the Artificial Intestinal Juice

In the clinical setting, SPS and other drugs are often taken simultaneously. We investigated the changes in the amounts of potassium ions and concomitant drugs adsorbed onto SPS when they coexist to elucidate the effect of concomitant drugs on the potassium ion adsorption onto SPS. As shown in Fig. 5, the saturation of amlodipine besylate and nifedipine adsorptions was reached after a minute and approximately 2 h, respectively. Therefore, adsorption experiments under the coexistence of potassium ions and amlodipine besylate or nifedipine, were evaluated until 10 min and 4 h, respectively. The amount of potassium ions adsorbed in each initial concentration under coexistence with amlodipine besylate and nifedipine are shown in Figs. 7 and 8, respectively. From the results, the saturation amounts of potassium ion adsorbed, under coexistence with concomitant drugs, were not different from when only potassium ions are present. Figures 9 and 10 indicate the residual rates of amlodipine besylate and nifedipine after adsorption by SPS in coexistence with potassium ions. The amount of amlodipine besylate adsorbed under the coexistence of each concentration of potassium ions decreased a little compared to when only the drug is present. On the other hand, the amount of nifedipine adsorbed under the coexistence of potassium ions did not decrease compared to when only the drug is present.

Fig. 7. Amount of Potassium Ion Adsorption under Coexistence of Amlodipine Besylate in the Artificial Intestinal Juice

Initial concentration: 1000–4000 mg/L (potassium ion), 10 mg/L (amlodipine besylate), solution volume: 500 mL, adsorbent: 2.5 g, elapsed time: 10, 20, 30 s, and 1, 3, 5, 10 min, temperature: 37 °C, agitation speed: 100 rpm.

Fig. 8. Amount of Potassium Ion Adsorption under Coexistence of Nifedipine in the Artificial Intestinal Juice

Initial concentration: 1000–4000 mg/L (potassium ion), 40 mg/L (nifedipine), solution volume: 500 mL, adsorbent: 2.5 g, elapsed time: 30 s, and 1, 10, 30, 60 min, and 2, 4h, temperature: 37 °C, agitation speed: 100 rpm.

Fig. 9. Amount of Amlodipine Besylate onto SPS under Coexistence of Potassium Ion in the Artificial Intestinal Juice

Initial concentration: 10 mg/L (amlodipine besylate), 1000–4000 mg/L (potassium ion), volume: 500 mL, adsorbent: 2.5 g, elapsed time: 10, 20, 30 s, and 1, 3, 5, 10 min, temperature: 37 °C, agitation speed: 100 rpm.

Fig. 10. Amount of Nifedipine onto SPS under Coexistence of Potassium Ion in the Artificial Intestinal Juice

Initial concentration: 40 mg/L (nifedipine), 1000–4000 mg/L (potassium ion), volume: 500 mL, adsorbent: 2.5 g, elapsed time: 30 s, and 1, 10, 30, 60 min, and 2, 4 h, temperature: 37 °C, agitation speed: 100 rpm.

Discussion

SPS has long been used as a therapeutic medicine for mild and chronic hyperkalemia.⁶⁾ SPS improves serum potassium levels by exchanging sodium ions for potassium ions in the digestive tract. This ion-exchange reaction occurs on the basis of the selectivity of polystyrene sulfonate resin for metal ions, particularly its higher affinity for potassium ions than sodium ions.¹⁸⁾ SPS also has the potential to adsorb concomitant drugs of SPS, instead of only potassium ions. The FDA reported that SPS may bind to other drugs in the digestive tract in 2017.⁹⁾ However, there are not many reports on the ability of drug adsorption with SPS. Reports that evaluate the effects of the drug adsorption of SPS on the original efficacy of SPS hardly exist. To the best our knowledge, this is the first study that investigated the adsorption capability of SPS to its concomitant drugs and the effects of these reactions on the efficacy of SPS.

The amount of potassium ions adsorbed onto SPS 6 h after stirring began was 39.1–69.8 mg/g (1.00–1.79 mEq/g). On the other hand, the potassium exchange capacity of SPS is defined as 110–135 mg/g (2.81–3.45 mEq/g) according to the JP XVIII.¹³⁾ We considered that the reason, why amounts adsorbed of potassium ion in this study were different from the potassium exchange capacity in JP XVIII, was based on the difference in the condition of each experiment. Firstly, there is the difference of initial concentration. In the present study, we determined initial concentration of potassium ion 1000–4000 mg/L considering the effect of meals.¹⁴⁾ Consequently, these concentrations were different from the ones of the experiment in the JP XVIII. Secondly, there is the presence or absence of coexistent ions. The artificial intestinal juice used in our experiments contains approximately 1610 mg/L of sodium ions. That is, amounts of potassium ion adsorbed onto SPS may have decreased because the desorption reaction of sodium ion from SPS was inhibited. From the above, we considered that the difference of experimental conditions and the presence of the coexist ion decreased the amount of potassium ion adsorbed onto SPS in our study.

SPS also has the potential to bind to its concomitant drugs. Several studies have reported that SPS has the ability to adsorb drugs, such as antidepressants, miglitol, anti-hypertensive agents, and more.^10,11,19) In the present study, we evaluated the adsorption capabilities of SPS to drugs commonly used concomitantly with SPS. In our results, amlodipine besylate, and nifedipine adsorbed onto SPS well. In contrast, azosemide and febuxostat did not really adsorb onto SPS. Furosemide was not adsorbed onto SPS at all. Amlodipine besylate dissociates into amlodipine and benzenesulfonic acid in the artificial intestinal juice. It is well known that most of amlodipine exists a cationic form at physiological pH condition (around pH 7.4) because the pK_a value of amlodipine is approximately 9.3.²⁰⁾ On the other hand, the pK_a value of benzenesulfonic acid is approximately 0.7. Therefore, we considered that amlodipine and benzenesulfonic acid existed as a cationic form and an anionic form, respectively in the artificial intestinal juice condition.

That is, in fact, it was considered that in fact, only amlodipine was adsorbed onto SPS and benzenesulfonic acid was not. On the other hand, furosemide, azosemide and febuxostat charged negatively in the artificial intestinal juice. Nifedipine did not have an electrical charge. Ohta et al. reported that cationic drugs are easily adsorbed onto polystyrene sulfonate drugs, regardless of their hydrophobicity, but the amounts of anionic and non-ionic drugs adsorbed onto polystyrene sulfonate drugs depend on their hydrophobicity.¹⁰⁾ Results obtained from our experiments had an almost similar trend with the previous study. Moreover, we considered that benzenesulfonic acid had little effect on the adsorption reaction of amlodipine onto SPS because of its anionic property. In the present study, amounts adsorbed of several drugs were lower than the results in previous works. Particularly, furosemide was never adsorbed in our study nevertheless the FDA had reported about the possibility of furosemide adsorption onto SPS. We could not compare the difference of adsorption results because the FDA did not show conditions about adsorption experiments at all. However, we considered that furosemide might be adsorbed onto SPS under the artificial gastric juice condition (pH 1.2) because of its pK_a is approximately 3.6. On the other hand, Ohta et al. reported that the rate of furosemide adsorbed onto CPS was less than 10% in pH 6.8 condition.¹⁰⁾ In this study, we used “preparations” of each drug used in the clinical setting and in the previous studies, “reagents” of each drug were used. Therefore, we considered that one of the possible reasons, why the amounts adsorbed in our study decreased than the ones in the previous studies, might be the effects of additives in the drug preparations. Nevertheless, we could not elucidate what additives affect the adsorption reaction onto SPS. In addition, there could be other factors which affect the drug adsorption onto SPS. Therefore, we need to keep investigating the behavior of drugs adsorption onto SPS. In our investigation, it was elucidated that the adsorption potential of SPS to its concomitant drugs under conditions proximate to the real clinical situation than any other studies.

In general, many of adsorption rate in the aqueous phase often fits either into the pseudo-first order model or the pseudo-second order model. These models were proposed by Lagergren in 1898 and by Ho and McKay in 1999.^16,17) Fitting into the pseudo-first model and the pseudo-second model can explain whether the adsorption reaction is based on surface adsorption or on internal diffusion reactions, respectively.²¹⁾ From the results, higher correlation coefficients of the pseudo-second order model (r = 0.992–1.000) were obtained in all drugs (except furosemide). Therefore, it was suggested that the adsorption reaction onto SPS was due to the internal diffusion process of the adsorbate to SPS. However, in amlodipine besylate, the intercept of linear formula of the pseudo-second order model, shown in Eq. (4), indicated a negative value (−0.016). Hence, it was suggested that adsorption kinetics of amlodipine besylate completely may not be conformed to the pseudo-second order model. In the present study, only dissociated amlodipine belongs to cationic drugs. Hence, we considered that the non-conforming of the amlodipine besylate adsorption onto SPS to the pseudo-second order model might be based on the difference of adsorption mechanism of amlodipine besylate and others.

We also reported that the use of some oral drugs concomitantly with SPS may increase serum potassium levels after SPS treatment.¹²⁾ We considered that the potassium ions and the drug might bind onto SPS competitively. In this study, we elucidated that SPS has adsorption abilities for its concomitant drugs in the digestive tract. To confirm this, we investigated the effect of potassium ions and concomitant drugs on the adsorption abilities of SPS. Results showed that the amount of potassium ions adsorbed remained constant whether amlodipine besylate or nifedipine was present or not. Similarly, the amount of nifedipine adsorbed remained constant whether potassium ions were present or not. On the contrary, the amount of amlodipine besylate adsorbed under the coexistence of potassium ions decreased compared to when only the drug was present. SPS is a cation-exchange resin. The main mechanism of potassium ion adsorption of SPS is through ion-exchange reactions, and mechanism of drug adsorption onto SPS is believed to be hydrophobic interactions, in addition to ionic interactions.¹⁰⁾ As previously stated, dissociated amlodipine and nifedipine are a cationic and a non-ionic drug, respectively. Therefore, it was considered that the adsorption mechanism of each drug onto SPS may be partially different. In other words, we considered that nifedipine was adsorbed onto SPS by hydrophobic interactions, while amlodipine besylate was adsorbed onto SPS not only by hydrophobic interactions, but also by ionic interactions. Results suggested that there might be competition in the adsorption between potassium ions and amlodipine besylate. However, the amount of potassium ions adsorbed did not decrease under the coexistence with amlodipine besylate. We considered that SPS could have a higher affinity for potassium ions than amlodipine besylate. This difference may be related to various factors, including ionic size.

SPS showed the capability to adsorb potassium ions in artificial intestinal juice. Several drugs used concomitantly with SPS had potentials to be adsorbed onto SPS in the digestive tract. In the clinical setting, some drug preparations release their components bit by bit in the digestive tract over a long period of time. If those drugs coexist with SPS, not only can the released components be adsorbed onto SPS, but the expected effects may not be obtained. Therefore, we need to continue investigating the interaction between SPS and its concomitant drugs for better prescription to CKD patients.

Conclusion

In this study, we proved the adsorption ability of potassium ion onto SPS quantitatively and qualitatively, and our results also clarified that SPS has the potential to adsorb drugs used concomitantly with SPS in the digestive tract. From the results of the adsorption kinetics analysis, the adsorption of potassium ions and of each drug (except furosemide and amlodipine besylate) onto SPS was based on the pseudo-second order model and on the internal diffusion process might be involved with the adsorption reaction of SPS. Moreover, we also verified about the effects of the potassium coexistence on the adsorption behavior of drugs onto SPS for the first time. As the results, we also elucidated that the mechanism of adsorption of potassium ions and drugs onto SPS might be partially similar. That is, the coexistence of SPS and other oral drugs might decrease the efficacy of not only SPS, but also of other drugs. Thus, the medical staff, particularly pharmacists, have to consider the possibility of the interaction between SPS and its concomitant drugs to suggest the appropriate prescriptions for hyperkalemia patients with CKD. In addition, there are many drugs used concomitantly with SPS other than ones indicated in this study in the clinical situation. Hence, it is necessary for us to continue investigating about drug interaction between SPS and its concomitant drugs in the digestive tract.

Conflict of Interest

The authors declare no conflict of interest.

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