Linaclotide is a 14-amino-acid synthetic peptide (MW ~1526.8 g/mol) structurally related to the endogenous guanylin and uroguanylin peptides, containing three intramolecular disulfide bonds. It was FDA-approved in August 2012 for irritable bowel syndrome with constipation (IBS-C) in adults and chronic idiopathic constipation (CIC) in adults. Linaclotide is a guanylate cyclase-C (GC-C) agonist that acts locally in the intestinal lumen with minimal systemic absorption, increasing intestinal fluid secretion and reducing visceral pain signaling.
Category: Gastrointestinal / GC-C Agonist. Evidence rating: A (strong human clinical data).
Clinical status: FDA-approved (Linzess for IBS-C and CIC, August 2012)
Linaclotide binds to and activates GC-C on the luminal surface of intestinal epithelial cells, stimulating intracellular cGMP production. Intracellular cGMP activates the CFTR chloride channel, increasing secretion of chloride, bicarbonate, and water into the intestinal lumen, which accelerates…
Safety considerations: Most common adverse event: diarrhea (16-20% in IBS-C trials; severe diarrhea leading to discontinuation in 4-5%); Abdominal pain, flatulence, and abdominal distension reported; Minimal systemic side effects due to negligible absorption.
Reviewed by the PeptideAtlas Editorial Team.
| Molecular weight | ~1526.8 g/mol |
|---|---|
| CAS number | 851199-59-2 |
| Half-life | Not applicable (acts locally; minimal systemic absorption; active metabolite MM-419447 produced in GI lumen) |
| Production method | synthetic |
| Anti-doping status | not-listed |
| US regulatory status | FDA-approved. Linzess approved August 2012. Available in 72 mcg (CIC), 145 mcg (CIC), and 290 mcg (IBS-C) capsules. |
Related peptides: Plecanatide.
Taking linaclotide with food can increase the incidence and severity of diarrhea. Administration on an empty stomach at least 30 minutes before the first meal of the day reduces the risk of diarrhea and provides more consistent drug delivery to the intestinal epithelium.
Beyond its secretory effects, linaclotide stimulates the release of cGMP from intestinal epithelial cells into the submucosal space. This extracellular cGMP acts on pain-sensing colonic afferent nerves to reduce visceral hypersensitivity, which is a key feature of IBS. This analgesic mechanism is distinct from and additive to the motility effects.
Diarrhea is the most common side effect, occurring in 16-20% of IBS-C patients (vs 3-6% placebo). Severe diarrhea leading to discontinuation occurred in about 4-5%. The 145 mcg CIC dose has a lower diarrhea rate. Starting at the lower dose and taking it on an empty stomach can help.