Endotoxin-binding affinity of sevelamer hydrochloride.

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-alpha 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-alpha 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.