Summary

Linaclotide is a 14-amino-acid synthetic peptide agonist of guanylate cyclase-C (GC-C), approved by the FDA and EMA in 2012 (Linzess/Constella) for irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC). Acting locally within the intestinal lumen with negligible systemic absorption, linaclotide increases fluid secretion and accelerates intestinal transit while also reducing visceral pain. This profile is for research and educational purposes only.

Mechanism

Linaclotide is a potent agonist of guanylate cyclase-C (GC-C), a transmembrane receptor expressed on the luminal surface of intestinal enterocytes. GC-C activation increases intracellular cyclic guanosine monophosphate (cGMP). cGMP activates the cystic fibrosis transmembrane conductance regulator (CFTR), leading to chloride and bicarbonate secretion into the intestinal lumen, with accompanying water efflux, accelerating intestinal transit. Additionally, cGMP is released extracellularly and is thought to modulate visceral pain pathways, contributing to linaclotide's abdominal pain reduction effect. Due to its large size and peptide structure, linaclotide is not significantly absorbed systemically.

Evidence base

Linaclotide has strong evidence from four pivotal phase 3 trials across IBS-C (n=1,602) and CIC (n=1,276), plus long-term extension data and a paediatric trial. Efficacy on the FDA composite IBS-C endpoint is well established. Safety profile is well characterised with diarrhoea as the primary adverse effect. Systemic absorption is negligible, distinguishing it from most peptide therapeutics.

Protocols

Linaclotide is a licensed prescription medicine. In clinical practice, 290 mcg is administered orally once daily for IBS-C and 145 mcg once daily for CIC, taken 30 minutes before the first meal. These protocols are described for research reference only and do not constitute dosing advice.

Linaclotide is classified as a Prescription-Only Medicine (POM) in the United Kingdom. Constella is licensed by the MHRA for IBS-C and CIC. Supply without a prescription is unlawful.

Vendor notes

Linaclotide is a licensed POM available only through registered pharmacies with a valid prescription. We do not list research-grade vendors for this compound. Researchers requiring linaclotide for in vitro or animal studies should source from established biochemical supply companies with appropriate COAs.

References

  1. Chey WD, Lembo AJ, Lavins BJ, et al. Linaclotide for irritable bowel syndrome with constipation: a 26-week, randomized, double-blind, placebo-controlled trial. Am J Gastroenterol. 2012;107(11):1702-1712.
  2. Rao S, Lembo AJ, Shiff SJ, et al. A 12-week, randomized, controlled trial with a 4-week randomized withdrawal period to evaluate the efficacy and safety of linaclotide in irritable bowel syndrome with constipation. Am J Gastroenterol. 2012;107(11):1714-1725.
  3. Lembo AJ, Schneier HA, Shiff SJ, et al. Two randomized trials of linaclotide for chronic constipation. N Engl J Med. 2011;365(6):527-536.
  4. Lembo AJ, Katz LD, Carmichael BJ, et al. Long-term efficacy and safety of linaclotide in patients with irritable bowel syndrome with constipation. Gastroenterology. 2014;147(5):S-727.
  5. Quigley EMM, Hornby PJ, Garcia JD, et al. Linaclotide in pediatric patients with irritable bowel syndrome with constipation. N Engl J Med. 2023;388(8):681-691.