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Linaclotide

Also known as: Linzess, Constella, GC-C agonist, MD-1100, linaclotide acetate

Guanylate cyclase-C (GC-C) agonist; synthetic 14-amino acid peptide; secretagogue; intestinal chloride channel activator

Research chemicalLast updated: October 10, 2026Based on 1 peer-reviewed studyPreclinical data only — no human trials
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What it is

Linaclotide (brand names Linzess, Constella) is a prescription capsule for adults with irritable bowel syndrome with constipation (IBS-C) or chronic idiopathic constipation. It activates GC-C receptors in the gut lining to increase fluid secretion and reduce pain signaling — with virtually no systemic absorption. FDA-approved since 2012.

The scientific side

linaclotide is a synthetic 14-amino acid peptide that acts as a potent and highly selective agonist of guanylate cyclase-C (GC-C) receptors expressed on intestinal epithelial cells. Upon oral administration, linaclotide binds to GC-C receptors on the luminal surface of the intestinal epithelium and activates the enzyme, stimulating intracellular production of cyclic guanosine monophosphate (cGMP). Elevated intracellular cGMP activates the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel, resulting in increased secretion of chloride and bicarbonate ions into the intestinal lumen. This osmotically drives water secretion, thereby accelerating intestinal transit and softening stool consistency — the primary mechanism underlying its efficacy in CIC and IBS-C. A critical and mechanistically distinct second action involves the efflux of cGMP into the submucosal compartment, where it acts on afferent nociceptive neurons to reduce the activity of pain-signaling fibers. This peripheral analgesic mechanism is independent of the secretory effect and is supported by both preclinical and clinical data showing linaclotide reduces visceral hypersensitivity and abdominal pain in IBS-C patients. Because linaclotide is minimally absorbed from the gastrointestinal tract — with plasma levels essentially undetectable at therapeutic doses — its pharmacological effects are confined to the gut, which substantially limits systemic adverse effects. The drug and its active metabolite MM-419447 are not measurable in breast milk following standard doses. The endogenous GC-C ligands guanylin and uroguanylin share this receptor, suggesting linaclotide pharmacologically amplifies a physiological regulatory pathway for intestinal fluid homeostasis and potentially pain modulation. Collectively, the dual secretory and analgesic mechanisms of GC-C agonism position linaclotide as a mechanistically novel treatment for constipation-associated functional bowel disorders.

Class: Guanylate cyclase-C (GC-C) agonist; synthetic 14-amino acid peptide; secretagogue; intestinal chloride channel activator

Administration & storage

Storage
Store at room temperature 20–25°C (68–77°F). Excursions permitted to 15–30°C (59–86°F). Keep in the original container with the desiccant. Do not remove desiccant packet from bottle. Keep bottle tightly closed. Protect from moisture.
Cautions
BOXED WARNING (FDA): Linaclotide is contraindicated in patients less than 6 years of age — neonatal mouse studies demonstrated dose-dependent deaths from severe fluid loss and dehydration. Avoid use in patients aged 6 to less than 18 years of age (limited data).,Most common adverse reaction is diarrhea, reported in approximately 20% of IBS-C patients and up to 19% of CIC patients receiving 145 µg. Diarrhea is the leading cause of treatment discontinuation (4.0% of patients in RCTs).,If severe diarrhea occurs, withhold linaclotide and rehydrate the patient. Severe diarrhea causing dehydration was reported in Phase 3 trials including one pediatric hospitalization (PMID 38211604).,Use with caution in patients with known or suspected mechanical bowel obstruction — linaclotide increases intestinal fluid secretion and transit.,Linaclotide is not systemically absorbed at therapeutic doses; therefore drug-drug interactions via systemic pharmacokinetic pathways are not expected.,No dose adjustment required for hepatic or renal impairment due to negligible systemic absorption.

Legal & regulatory status

US FDA

FDA-approved (NDA 202811) as Linzess (linaclotide) capsules for irritable bowel syndrome with constipation (IBS-C) at 290 µg once daily and for chronic idiopathic constipation (CIC) at 145 µg or 72 µg once daily in…

WADA

Linaclotide is not listed on the WADA Prohibited List. It acts locally in the gut with negligible systemic absorption and has no known performance-enhancing applications in competitive sport.

Health Canada

Approved in Canada under the brand name Constella (linaclotide) for the treatment of adults with IBS-C and CIC. Listed in Canadian gastroenterology guidelines as a secretagogue treatment option.