Bile acid binding to sevelamer HCl

Braunlin, William H.; Zhorov, Eugene; Guo, Amy; Apruzzese, William; Xu, Qiuwei; Hook, Patrick; Smisek, David L.; Mandeville, W. Harry; Holmes‐Farley, S. Randall

doi:10.1046/j.1523-1755.2002.00459.x

Cited by 98 publications

(76 citation statements)

References 21 publications

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“…However, it is possible that the concomitant administration of phosphate binders with oral VDRAs may result in drug-drug interactions, thereby reducing the therapeutic activity of these oral VDRAs. Preclinical studies have shown that sevelamer (SEV) hydrochloride (Renagel®) has a high affinity for bile acids, which may impair the absorption of fat-soluble vitamins, including vitamin D [6]. Furthermore, a pharmacokinetic study in healthy human subjects found that SEV binds to exogenous oral calcitriol, reducing its bioavailability [7].…”

Section: Introductionmentioning

confidence: 99%

Pharmacodynamic Effects of Sucroferric Oxyhydroxide and Sevelamer Carbonate on Vitamin D Receptor Agonist Bioactivity in Dialysis Patients

Sprague

Covic²,

Floege³

et al. 2016

Am J Nephrol

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Background: Many patients with chronic kidney disease are prescribed vitamin D receptor agonists (VDRAs) for the management of secondary hyperparathyroidism. Oral phosphate binders may interact with, and potentially reduce the therapeutic activity of, oral VDRAs. This post hoc analysis of a Phase 3 study evaluated the pharmacodynamic effects of the iron-based phosphate binder sucroferric oxyhydroxide (SFOH) and sevelamer (SEV) carbonate on VDRA activity in dialysis patients. Methods: One thousand and fifty nine patients were randomized to SFOH 1.0-3.0 g/day (n = 710) or SEV 2.4-14.4 g/day (n = 349) for up to 52 weeks. Potential interactions of SFOH and SEV with VDRAs were assessed using serum intact parathyroid hormone (iPTH) concentrations as a pharmacodynamic biomarker. Three populations of SFOH- and SEV-treated patients were analyzed: Population 1 (n = 187), patients taking concomitant stable doses of oral VDRAs only; Population 2 (n = 250), patients taking no concomitant VDRAs; Population 3 (n = 68), patients taking concomitant stable doses of intravenous paricalcitol only. Populations were compared using a mixed-effects model to obtain the least squares mean change in iPTH from baseline to Week 52. Differences between treatment groups were also compared. Results: In Population 1, iPTH decreased from baseline to Week 52 in the SFOH group (-25.3 pg/ml) but increased in the SEV group (89.8 pg/ml) (p = 0.02). In Population 2, iPTH increased to a similar extent in both treatment groups. In Population 3, iPTH concentrations in both treatment groups decreased to a similar degree (-29.6 and -11.4 pg/ml for SFOH and SEV, respectively; p = 0.87). Conclusions: In contrast with SEV, SFOH did not appear to impact the iPTH-lowering effect of oral VDRAs.

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Section: Introductionmentioning

confidence: 99%

Pharmacodynamic Effects of Sucroferric Oxyhydroxide and Sevelamer Carbonate on Vitamin D Receptor Agonist Bioactivity in Dialysis Patients

Sprague

Covic²,

Floege³

et al. 2016

Am J Nephrol

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“…Our meta-analysis indicated that sevelamer was significantly more effective than CBPBs in lowering serum TC and LDL. This is apparently due to the binding of sevelamer to bile acids in the intestine, similar to the effect of bile acid sequestrants such as cholestyramine, colestipol, and colesevelam [36]. The resulting loss of bile acids from the enterohepatic circulation and increase in bile acid excretion lead to depletion of hepatic cholesterol and an increase in LDL cholesterol clearance from circulation [36] .…”

Section: Discussionmentioning

confidence: 99%

“…This is apparently due to the binding of sevelamer to bile acids in the intestine, similar to the effect of bile acid sequestrants such as cholestyramine, colestipol, and colesevelam [36]. The resulting loss of bile acids from the enterohepatic circulation and increase in bile acid excretion lead to depletion of hepatic cholesterol and an increase in LDL cholesterol clearance from circulation [36] . It has been suggested that lipid disorders may be related to CAC and atherosclerosis in dialysis patients [37,38].…”

Section: Discussionmentioning

confidence: 99%

Meta-Analysis Comparing Sevelamer and Calcium-Based Phosphate Binders on Cardiovascular Calcification in Hemodialysis Patients

Zhang

Li²,

Lu³

et al. 2010

Nephron Clin Pract

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Background: Accelerated cardiovascular calcification often occurs in patients with cardiovascular disease who are on hemodialysis. We performed a meta-analysis to compare the effects of sevelamer hydrochloride and calcium-based phosphate binders on coronary artery calcification, C-reactive protein, alkaline phosphatase and intact parathyroid hormone in patients undergoing hemodialysis. Methods: We used the key words ‘sevelamer’ and ‘Renagel’ to retrieve studies from Medline, the Cochrane Library and conference proceedings. The trials searched were evaluated for eligibility and quality, and then the data were abstracted and analyzed. Results: We ultimately included 14 studies that enrolled a total of 3,271 patients. There was no difference in coronary artery calcium progression between the calcium and the sevelamer groups. Use of sevelamer, rather than calcium-based phosphate binders, was associated with significantly lower C-reactive protein levels (weighted mean difference (WMD) –1.42; 95% confidence interval (CI) –2.09 to –0.74), higher alkaline phosphatase levels (WMD 22.66; 95% CI 13.81–31.5) and higher intact parathyroid hormone levels (WMD 55.85; 95% CI 14.47–97.24). Conclusions: Treatment with sevelamer did not affect cardiovascular calcification, but there was a trend for lower C-reactive protein levels, higher alkaline phosphatase levels and intact parathyroid hormone levels among sevelamer-treated patients.

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“…Sevelamer hydrochloride also exhibits bile acid-binding propertiesin vitro [4], which result clinically in LDL cholesterol lowering [5]. Sevelamer hydrochloride has also been shown to bind other organic anions including indoxyl sulfate [6] and uric acid [7].…”

Section: Discussionmentioning

confidence: 99%

“…This effective calcium-free phosphate binder has been used for the treatment of hyperphosphatemia in patients with chronic kidney failure [3]. Sevelamer hydrochloride has also been shown to bind other compounds in the intestinal tract including bile acids [4], which results in the lowering of LDL cholesterol [5], as well as other organic anions such as the uremic toxin indoxyl sulfate [6] and uric acid [7]. When administered concomitantly, sevelamer hydrochloride can also reduce the oral bioavailability of drugs such as ciprofloxacin and thyroxine [8, 9].…”

Section: Introductionmentioning

confidence: 99%

Endotoxin-Binding Affinity of Sevelamer Hydrochloride

Perianayagam

Jaber²

2008

Am J Nephrol

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Background: Sevelamer hydrochloride has been shown to attenuate circulating biomarkers of inflammation in patients with chronic kidney failure. We hypothesize that sevelamer hydrochloride binds bacterial endotoxin (ET) resulting in a decrease in ET levels and cytokine production. Methods: To assess the ET-binding affinity of sevelamer hydrochloride, purified Escherichia coli ET was incubated with sevelamer hydrochloride (0–50 mg/ml). After incubation, ET was measured in supernatants. In addition, THP-1-derived monocytes were co-incubated with supernatants of sevelamer hydrochloride and ET. After 24-hour incubation, TNF-α was measured. The effect of pH on the ET-binding affinity of sevelamer hydrochloride, as well as cooperative binding between ET and phosphate for sevelamer hydrochloride were assessed. Results: Sevelamer hydrochloride exhibited time- and dose-dependent binding affinity for ET, resulting in a marked reduction in free ET levels. The 1-hour dose-dependent ET-binding effect of sevelamer hydrochloride translated into a marked reduction in TNF-α levels. Varying the pH conditions did not affect the ET-binding affinity of sevelamer hydrochloride. The addition of phosphate (0–50 mM) resulted in a further reduction in free ET levels, translating into a further increase in the binding affinity of sevelamer hydrochloride for ET. Conclusions: This study demonstrates that sevelamer hydrochloride binds to ET, thereby reducing free ET and cytokine levels. Positive cooperative binding was also noted between phosphate and ET for sevelamer hydrochloride. This study supports the hypothesis that sevelamer hydrochloride might bind to ET in the intestinal lumen and reduce systemic inflammation. Animal and human studies are required to examine this hypothesis.

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Bile acid binding to sevelamer HCl

Abstract: The favorable bile acid binding characteristics of sevelamer provide a compelling explanation for its ability to lower LDL cholesterol in hemodialysis patients and in healthy volunteers.

Cited by 98 publications

References 21 publications

Pharmacodynamic Effects of Sucroferric Oxyhydroxide and Sevelamer Carbonate on Vitamin D Receptor Agonist Bioactivity in Dialysis Patients

Pharmacodynamic Effects of Sucroferric Oxyhydroxide and Sevelamer Carbonate on Vitamin D Receptor Agonist Bioactivity in Dialysis Patients

Meta-Analysis Comparing Sevelamer and Calcium-Based Phosphate Binders on Cardiovascular Calcification in Hemodialysis Patients

Endotoxin-Binding Affinity of Sevelamer Hydrochloride

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