Linaclotide (marketed under the trade name Linzess and Constella) is a peptide agonist of the guanylate cyclase 2C (GC-C). Once linaclotide and its active metabolite binds to GC-C, it has local effect on the luminal surface of the intestinal epithelium. Activation of GC-C by linaclotide results in the intra- and extracellular increase of cyclic guanosine monophosphate concentrations (cGMP). This elevation of cGMP levels stimulates the secretion of chloride and bicarbonate into the intestinal lumen via activation of cystic fibrosis transmembrane conductance regulator (CFTR) ion channel. The metabolite of linaclotide MM-419447 (CCEYCCNPACTGC) contributes to the pharmacologic effects of linaclotide. Ultimately, linaclotide helps patients with IBS (especially with constipation) as GI transit is accelerated and the release of intestinal fluid is increased. In animal models, a decrease in visceral pain after administration of linaclotide may be observed. A decrease in the activity of pain-sensing nerves occurs as a result of an increase in extracellular cGMP. It was approved by the FDA in August 2012 for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation (IBS-C) in adults.
The acetate salt form of linaclotide, a synthetic, fourteen amino acid peptide and agonist of intestinal guanylate cyclase type C (GC-C), which is structurally related to the guanylin peptide family, with secretagogue, analgesic and laxative activities. Upon oral administration, linaclotide binds to and activates GC-C receptors located on the luminal surface of the intestinal epithelium. This increases the concentration of intracellular cyclic guanosine monophosphate (cGMP), which is derived from guanosine triphosphate (GTP). cGMP activates the cystic fibrosis transmembrane conductance regulator (CFTR) and stimulates the secretion of chloride and bicarbonate into the intestinal lumen. This promotes sodium excretion into the lumen and results in increased intestinal fluid secretion. This ultimately accelerates GI transit of intestinal contents, improves bowel movement and relieves constipation. Increased extracellular cGMP levels may also exert an antinociceptive effect, through an as of yet not fully elucidated mechanism, that may involve modulation of nociceptors found on colonic afferent pain fibers. Linaclotide is minimally absorbed from the GI tract.
