NHE3 (sodium/hydrogen exchanger isoform 3)

Class

Minimally-absorbed small-molecule NHE3 inhibitor

Pathway

Intestinal paracellular sodium/phosphate absorption (hyperphosphatemia on dialysis; IBS-C sodium transport for the Ibsrela indication)

NHE3, the sodium/hydrogen exchanger isoform 3, is a transporter embedded in the brush-border membrane of intestinal epithelial cells (and also present in the kidney), where it normally pulls sodium out of the gut lumen into the body in exchange for hydrogen ions. This absorption of sodium is a major driver of water uptake from the intestine and also facilitates the passive absorption of phosphate through gaps between epithelial cells, a route called the paracellular pathway. Inhibiting NHE3 locally in the gut reduces sodium uptake, which has two distinct downstream consequences relevant to disease. First, less sodium absorption means more water and sodium remain in the intestinal lumen, softening stool and increasing bowel movement frequency, which is useful in constipation-predominant conditions. Second, altering sodium handling and epithelial tight-junction dynamics reduces how much dietary phosphate the paracellular pathway lets through, which matters for patients who cannot adequately excrete phosphate through their kidneys. Because the inhibitor used for this target is designed to stay largely within the intestine rather than entering the bloodstream, its effects are concentrated on gut sodium handling rather than on the kidney's own NHE3-dependent sodium reabsorption.