Linaclotide is small peptide agonist of guanylate cyclase C receptors in the intestine and is used orally as treatment of chronic constipation and irritable bowel syndrome. Linaclotide has not been linked to serum enzyme elevations during treatment or to episodes of clinically apparent liver injury.


Linaclotide (lin ak’ loe tide) is 14 amino acid peptide that acts as an agonist of the guanylate cyclase C receptors in the intestine. Activation of this receptor by linaclotide increases cyclic guanosine monophosphate levels which lead to an increase in secretion of chloride and bicarbonate into the intestinal lumen, thus increasing fluid secretion and promoting intestinal transit. Linaclotide acts locally on the luminal side of enterocytes in the upper intestine and is minimally absorbed. Several clinical trials have shown that linaclotide increases the number of spontaneous bowel movements, improves stool consistency and can alleviate symptoms of chronic constipation including the constipation of irritable bowel syndrome. Linaclotide was approved for use in the United States in 2012 for irritable bowel syndrome with constipation as well as idiopathic chronic constipation. Linaclotide is available in capsules of 72, 145 and 290 mcg under the brand name Linzess. The recommended dose for chronic idiopathic constipation is 72 or 145 mcg once daily and for irritable bowel syndrome with constipation is 290 mcg once daily. It is contraindicated in children below the age of 6 years and is not recommended for use in children below the age of 18 years. Side effects include diarrhea (~20%), abdominal pain, bloating, flatulence and headache. Rare but potentially severe adverse events include severe dehydration particularly in children.


In clinical trials, linaclotide therapy was not associated with significant changes in serum enzyme levels or episodes of clinically apparent liver injury. Minor transient ALT elevations arose in <1% of persons receiving long-term linaclotide therapy for constipation. Since its approval and marketing, there have been no reports of symptomatic serum aminotransferase elevations or clinically apparent liver injury with jaundice attributable to linaclotide. Thus, liver injury from linaclotide must be rare if it occurs at all.

Likelihood score: E (unlikely cause of clinically apparent liver injury).

Mechanism of Injury

Linaclotide is largely active on the epithelial cells in the intestinal tract and has minimal absorption. The lack of systemic absorption and the low doses used (in microgram amounts) may account for its lack of liver injury.

Drug Class: Gastrointestinal Agents, Drugs for Constipation, Irritable Bowel Syndrome Agents



Linaclotide – Generic, Linzess®


Gastrointestinal Agents


Product labeling at DailyMed, National Library of Medicine, NIH



References updated: 13 May 2019

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