Linaclotide, developed for the treatment of constipation-predominant irritable bowel syndrome (IBS-C) and chronic constipation, is a potent and selective guanylate cyclase C agonist.

Linaclotide acts on guanylate cyclase-C receptors on the luminal membrane to increase chloride and bicarbonate secretions into the intestine, inhibit sodium ion absorption, enhance water secretion into the lumen, and improve defecation; the drug is minimally absorbed into the systemic circulation[2]. In vitro, linaclotide inhibits [125I]-STa binding to intestinal mucosal membranes from wt mice in a concentration-dependent manner, while binding to membranes from GC-C null mice significantly decreases. Linaclotide is completely degraded after a 30-minute incubation in jejunal fluid in vitro[1].

Linaclotide significantly increases weekly spontaneous bowel movements and complete spontaneous bowel movements (CSBMs) while reducing abdominal pain in patients with chronic constipation [2]. Pharmacokinetic analysis shows very low oral bioavailability (0.10%). In intestinal secretion and transit models, linaclotide exhibits significant pharmacological effects in wt, but not in GC-C null mice: increased fluid secretion into surgically ligated jejunal loops is accompanied by elevated cyclic guanosine-3',5-monophosphate levels and accelerated gastrointestinal transit [1].