Tenapanor Hydrochloride: A Comprehensive Monograph on a First-in-Class NHE3 Inhibitor for Gastrointestinal and Renal Disorders

Executive Summary

Tenapanor Hydrochloride is a first-in-class, minimally absorbed, small-molecule inhibitor of the intestinal Sodium/Hydrogen Exchanger 3 (NHE3).[1] This novel agent acts locally within the gastrointestinal tract to exert its therapeutic effects, representing a significant innovation in the management of distinct disorders in gastroenterology and nephrology. It is commercially available under two brand names, each targeting a separate indication:

Ibsrela for the treatment of Irritable Bowel Syndrome with Constipation (IBS-C) in adults, and Xphozah for the reduction of serum phosphorus in adults with Chronic Kidney Disease (CKD) on dialysis.[2]

The singular mechanism of NHE3 inhibition produces two distinct pharmacodynamic outcomes. For IBS-C, Tenapanor functions as a "retainagogue," reducing sodium absorption from the gut, which leads to an osmotic retention of water in the intestinal lumen. This action increases stool water content, softens stool consistency, and accelerates colonic transit, thereby alleviating the primary symptoms of constipation and abdominal pain associated with IBS-C.[5] For hyperphosphatemia in CKD, Tenapanor acts as a novel phosphate absorption inhibitor. Its inhibition of NHE3 is understood to induce conformational changes in intestinal tight junctions, reducing paracellular permeability specifically to phosphate and thereby decreasing its absorption from the diet. This mechanism is fundamentally different from traditional phosphate binders, which sequester phosphate within the gut lumen.[1]