Mechanism of Action of Sevelamer Hydrochloride
Sevelamer hydrochloride is a non-absorbed polymeric amine that binds dietary phosphate in the gastrointestinal tract through ionic and hydrogen bonding, preventing phosphate absorption and lowering serum phosphorus levels. 1
Primary Mechanism
Sevelamer contains multiple protonated amine groups that interact directly with phosphate molecules in the intestinal lumen through ionic and hydrogen bonding. 1
The drug is a crosslinked polymer (poly(allylamine hydrochloride) crosslinked with epichlorohydrin) in which approximately 40% of the amines are protonated, creating positively charged binding sites. 1
These protonated amines exist in their active form throughout the intestinal tract, where they sequester phosphate and enhance its fecal excretion rather than allowing systemic absorption. 1, 2
Sevelamer is not systemically absorbed—mass balance studies using radiolabeled sevelamer in healthy volunteers confirmed zero systemic absorption, eliminating risk of systemic toxicity. 1
Secondary Mechanisms (Pleiotropic Effects)
Sevelamer binds bile acids in the gastrointestinal tract through the same ion exchange mechanism, which explains its lipid-lowering effects. 1, 2
Bile acid sequestration triggers increased hepatic conversion of cholesterol to bile acids, resulting in 15-31% reductions in LDL cholesterol and total cholesterol observed within 2 weeks of treatment. 1, 2
The bile acid binding may interfere with normal fat absorption, potentially reducing absorption of fat-soluble vitamins A, D, and K—a clinically relevant consideration requiring monitoring and supplementation. 1
Recent evidence suggests sevelamer binds uremic toxins and inflammatory mediators in the intestinal lumen, contributing to decreased C-reactive protein levels and overall anti-inflammatory effects. 2, 3
Clinical Pharmacology Implications
Because sevelamer works exclusively in the intestinal lumen without systemic absorption, it avoids the calcium load associated with calcium-based phosphate binders, preventing hypercalcemia and reducing vascular calcification progression. 4, 2
The mechanism requires the drug to be present during phosphate exposure, which is why administration must occur with meals (specifically 10-15 minutes before or during meals) to maximize phosphate binding when dietary phosphate enters the GI tract. 4
The non-absorption profile means overdose risk is minimal—doses up to 14 g daily for 8 days in healthy volunteers and average doses up to 13 g daily in hemodialysis patients produced no systemic adverse effects. 1