What is the mechanism of Plecanatide?

Plecanatide is a medication primarily used for the treatment of chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C). Its mechanism revolves around its action as a guanylate cyclase-C (GC-C) agonist, which plays a pivotal role in regulating intestinal fluid and electrolyte balance.

Upon oral administration, plecanatide directly targets the epithelial cells lining the gastrointestinal tract. It mimics the function of uroguanylin, a naturally occurring human peptide, by binding to and activating the GC-C receptors located on the luminal surface of these cells. This activation triggers a series of intracellular events beginning with the conversion of guanosine-5’-triphosphate (GTP) to cyclic guanosine monophosphate (cGMP).

The elevation in intracellular cGMP leads to the opening of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channels. This opening results in the secretion of chloride and bicarbonate ions into the intestinal lumen. The movement of these ions creates an osmotic gradient that draws water into the lumen, promoting increased intestinal fluid secretion.

The increased fluid secretion softens the stool and enhances its passage through the colon, thereby alleviating symptoms of constipation. Concurrently, the heightened levels of cGMP also reduce the activation of pain-sensing nerves, providing relief from the abdominal pain often associated with IBS-C.

It is important to note that plecanatide is minimally absorbed into the systemic circulation and predominantly remains within the gastrointestinal tract, which contributes to its localized action and minimizes systemic side effects.

By understanding the specific interactions and pathways involved, researchers and healthcare providers can better appreciate how plecanatide functions to relieve constipation and improve bowel movements. This knowledge helps in optimizing its use in clinical practice, ensuring that patients benefit from its therapeutic effects while minimizing potential side effects.