Mechanism of reduced intestinal phosphate absorption by tenapanor: a hypothesis

Tenapanor, a selective inhibitor of the sodium/hydrogen exchanger isoform 3 (NHE3), was initially developed for the treatment of irritable bowel syndrome with constipation. Subsequent preclinical and clinical studies revealed its ability to reduce gastrointestinal phosphate absorption, leading to effective serum phosphate control with minimal pill burden in patients with kidney failure undergoing dialysis therapy. However, the precise mechanisms underlying NHE3 inhibition, its impact on phosphate handling and the primary site of action within the gastrointestinal tract remain incompletely understood. This review explores the hypothesis that tenapanor-induced NHE3 inhibition elevates the luminal pH via enhanced bicarbonate secretion in the colon, thereby altering phosphate speciation. Phosphate exists in the body as monovalent (H₂PO₄⁻) and divalent (HPO₄²⁻) anions, with the latter predominating under alkaline conditions. Although divalent anions are theoretically more prone to be absorbed from the gut lumen via the paracellular transport route because of the lumen-negative transepithelial potential, on the contrary recent studies have provided evidence that monovalent species are transported more efficiently and that paracellular phosphate permeability is suppressed at high luminal pH. We now propose that the net negative electrostatic environment within the paracellular pore pathway of tight junctions may selectively hinder divalent phosphate transport. This hypothesis aligns with prior findings that tenapanor does not alter the expression of tight junction proteins, suggesting a physicochemical rather than a structural basis for reduced permeability. Further investigations are warranted to determine whether the electrostatic properties of the paracellular pathway contribute to the phosphate-lowering effect of tenapanor.