Linaclotide

Linzess (US, Mexico), Constella (EU, UK, Canada), MD-1100, MM-419447 (active metabolite)

Recovery, repair & tissue

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Note on this profile. Linaclotide is an approved prescription medicine for constipation disorders, not a research-only compound. This page explains the published science. Community/self-directed use is essentially none documented; it is an oral capsule that never enters the bloodstream in meaningful amounts.

Summary

Class: Synthetic 14-amino-acid peptide with three disulfide bonds; a guanylate cyclase-C (GC-C) agonist modelled on the heat-stable enterotoxin of E. coli and the natural gut hormones guanylin and uroguanylin
Mechanism: Activates GC-C receptors on the surface of the intestinal lining, raising cGMP, which drives chloride and bicarbonate (and therefore water) into the gut lumen to soften stool and speed transit, while cGMP leaking from the cells quietens pain-sensing nerves
Routes studied: Oral capsule once daily, taken on an empty stomach at least 30 minutes before the first meal
Half-life: Not measurable: plasma levels are below detection after oral doses (<1% absorbed); the drug and its active metabolite act in the gut lumen and are degraded there
Storage: Room temperature (below 25–30 °C), in the original bottle with the desiccant, tightly closed; protect from moisture; do not repackage or subdivide
Regulatory status: Approved medicine (US Aug 2012; EU Nov 2012; UK, Canada, Mexico and many others); not approved in Australia or South Africa †

Doses are as reported in studies or by the community — never recommendations.

1What it is

Linaclotide is a drug born from a toxin. Certain E. coli strains cause traveller's diarrhoea by secreting a tiny, heat-stable peptide (STa) that locks onto a receptor called guanylate cyclase-C on the gut lining and floods the bowel with fluid. The same receptor is the normal target of two hormones the gut makes itself, guanylin and uroguanylin, which fine-tune fluid secretion after meals. Microbia (later Ironwood) designed linaclotide as a controlled version of this mechanism: a 14-amino-acid peptide, held in shape by three disulfide bonds so it survives stomach acid and digestive enzymes, that activates GC-C just enough to relieve constipation without causing the diarrhoea of the toxin.

It was approved in 2012 for irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC) in adults, and in 2023 became the first drug approved for functional constipation in children aged 6–17, extended to age 7+ for IBS-C in late 2025 and to age 2 and above for functional constipation in 2026. It is marketed by AbbVie (through its Allergan acquisition) with Ironwood in the US and as Constella in Europe. A closely related GC-C , plecanatide (Trulance), followed in 2017.

Community/self-directed use: essentially none documented.

2How it's thought to work

Linaclotide and its metabolite (MM-419447, which lacks the terminal tyrosine) bind GC-C on the apical (lumen-facing) surface of enterocytes throughout the small intestine and colon.

GC-C generates cyclic GMP inside the cell, activating protein kinase G II, which opens the CFTR chloride channel and inhibits sodium absorption. Chloride and bicarbonate flow into the lumen, water follows, stool softens and transit speeds up.

Some cGMP is pumped out of the cell into the gut wall, where it reduces the firing of pain-sensing (nociceptive) nerve fibres — a separate analgesic action shown in rodent visceral-pain models and proposed to explain the abdominal-pain benefit in IBS-C (Castro 2013, Gastroenterology).

Because the peptide is not absorbed, there are no systemic hormonal or drug-interaction effects.

A guanylate cyclase-C agonist modelled on an E. coli toxin. Binding on the lumen side of the gut lining opens a chloride channel; chloride and water follow into the gut, and stool softens.Schematic — not to scale

3What the research shows

Irritable bowel syndrome with constipation

Two phase 3 trials (n=800 and n=804; 12 and 26 weeks) of 290 µg daily met the FDA composite endpoint (≥30% abdominal pain reduction plus ≥1 additional complete spontaneous bowel movement per week, in the same week, for ≥6 of 12 weeks) in about 33–34% of patients vs 14–21% on placebo, with improvements in bloating, straining and stool consistency (Chey 2012, Am J Gastroenterol; Rao 2012, Am J Gastroenterol). Benefit was maintained to 26 weeks with no rebound after withdrawal beyond return of symptoms. [2][3]

Chronic idiopathic constipation

Two 12-week trials (n=1,276 combined) of 145 and 290 µg found ≥3 complete spontaneous bowel movements per week with an increase of ≥1 in 9 of 12 weeks in 16–21% vs 3–6% on placebo (Lembo 2011, NEJM). A later trial established the 72 µg dose (Lacy 2015, Am J Gastroenterol / Schoenfeld 2018). [1]

Paediatric functional constipation

A phase 3 trial in children aged 6–17 (n=328) showed 72 µg increased spontaneous bowel movement frequency by 2.2 per week vs 1.0 on placebo over 12 weeks, with a safety profile similar to adults (Di Lorenzo 2024, Lancet Gastroenterol Hepatol). Trials in younger children and in paediatric IBS-C supported the 2025–2026 expansions. [4]

Graded A (phase 2)

Opioid-induced constipation

Linaclotide improved bowel movement frequency in a 12-week phase 2 trial of patients on chronic opioids; not pursued to approval (Brenner 2020, Am J Gastroenterol). [7]

Graded C/D

Abdominal pain mechanism

Rodent models of visceral hypersensitivity show reduced nociceptor firing via extracellular cGMP (Castro 2013; Silos-Santiago 2013). Human mechanistic data rely on symptom scores. [5]

Graded C/D

Colorectal cancer chemoprevention

GC-C is a tumour-suppressor pathway and linaclotide-type reduce polyps in mouse models; a small human study showed target engagement in colon tissue (Weinberg 2017, Cancer Prev Res). Investigational only.

4Reported side effects and interactions

Literature-reported

diarrhoea is the main adverse effect (about 16–20% at 290 µg, 2–4% severe; ~2–5% discontinue because of it), usually starting in the first two weeks and often settling. Also abdominal pain, flatulence, abdominal distension, viral gastroenteritis and headache at rates close to placebo. Dehydration and electrolyte disturbance can follow severe diarrhoea. Faecal incontinence is reported, especially in children.

Community-reported

none documented.

Boxed warning (US). contraindicated in children under 2 years because neonatal mice died of dehydration after oral doses; the original warning covered under-6s and was revised with the paediatric approvals. In the EU the product is not recommended below the approved paediatric ages.

Contraindications. known or suspected mechanical gastrointestinal obstruction.

Theoretical. none systemic, given negligible absorption; no carcinogenicity signal.

Interactions. none pharmacokinetic (not absorbed, does not affect CYP enzymes). Clinically, other laxatives and prokinetics add to the effect; proton-pump inhibitors and NSAIDs were associated with slightly more diarrhoea in trials. Taking it with food increases diarrhoea, hence the empty-stomach instruction.

Markers researchers commonly monitor

No blood markers are specific to linaclotide because it is not absorbed. Trial and clinical monitoring is symptom-based:

Marker	Why it's watched
Stool diary (frequency, Bristol Stool Form, straining, completeness)	the trial endpoints and the practical measure of response; a 2–4-week trial usually shows whether it works.
Abdominal pain and bloating scores (0–10)	the IBS-C-specific outcome.
Hydration and, if diarrhoea is severe or prolonged, serum electrolytes (sodium, potassium, bicarbonate)	the only lab test with a rationale, particularly in children and the elderly.
Body weight in children	dehydration check during the first weeks.
Red-flag review (bleeding, weight loss, anaemia, nocturnal symptoms)	constipation drugs should not mask a missed diagnosis; this is a clinical check, not a lab.

Free for everyone. Safety information is never behind a paywall.

5Formulation and handling

Oral capsules (72, 145 and 290 µg) containing linaclotide-coated beads, taken once daily at least 30 minutes before the first meal. For people who cannot swallow capsules the contents can be sprinkled on a teaspoon of room-temperature applesauce or dispersed in 30 mL of water and swallowed immediately (or given via a nasogastric or gastrostomy tube) — the label describes this precisely. Capsules are moisture-sensitive and must stay in the original bottle with the desiccant; they should not be transferred to pill organisers. No calculator applies.

6Commonly studied alongside

Plecanatide (the other approved GC-C agonist), lubiprostone (a chloride-channel activator), prucalopride (a 5-HT4 prokinetic), tenapanor (an NHE3 inhibitor) and polyethylene glycol — the comparators in constipation guidelines. In this library the relevant neighbours are the gut peptides: BPC-157 and KPV (both research-only, with no overlapping mechanism), and the GLP-1 class (Semaglutide, Tirzepatide), whose constipation side effect is sometimes managed with linaclotide off-label.

Informational cross-links. Not stack recommendations.

7Regulatory status by region

Region	Status (checked —)
United States	FDA-approved (Linzess, Aug 2012) for adult IBS-C and CIC; paediatric functional constipation ages 6–17 (June 2023) and ages 2+ (2026); paediatric IBS-C ages 7+ (Nov 2025) †
European Union	EMA-authorised (Constella, Nov 2012) for moderate-to-severe IBS-C in adults; paediatric indications †
United Kingdom	MHRA-licensed (Constella); NICE-recommended for IBS-C when optimal laxatives have failed
Australia	Not TGA-registered as of review date †
South Africa	Not SAHPRA-registered as of review date †
Sport	Not on the WADA Prohibited List

8Open questions

Long-term outcomes in children, including growth and bowel habit after stopping.
How much of the pain benefit is a direct nerve effect versus relief of constipation.
Whether GC-C agonism has any role in colorectal cancer prevention in humans.
Comparative effectiveness versus plecanatide, prucalopride and tenapanor — few head-to-head trials exist.

9References

1Lembo AJ et al. (2011). Two randomized trials of linaclotide for chronic constipation. NEJM. PubMed · DOI
2Chey WD et al. (2012). Linaclotide for irritable bowel syndrome with constipation: a 26-week, randomized, double-blind, placebo-controlled trial to evaluate efficacy and safety. Am J Gastroenterol. PubMed · DOI
3Rao S et al. (2012). 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. PubMed · DOI
4Di Lorenzo C et al. (2024). Linaclotide for the treatment of functional constipation in children aged 6–17 years: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Gastroenterol Hepatol. PubMed
5Castro J et al. (2013). Linaclotide inhibits colonic nociceptors and relieves abdominal pain via guanylate cyclase-C and extracellular cyclic guanosine 3',5'-monophosphate. Gastroenterology. PubMed · DOI
6Busby RW et al. (2010). Linaclotide, through activation of guanylate cyclase C, acts locally in the gastrointestinal tract to elicit enhanced intestinal secretion and transit. Eur J Pharmacol. PubMed · DOI
7Brenner DM et al. (2020). Efficacy and safety of linaclotide for opioid-induced constipation in patients with chronic noncancer pain syndromes from a phase 2 randomized study. Pain / Am J Gastroenterol [verify journal]. PubMed · DOI
8AbbVie/Ironwood. Linzess (linaclotide) prescribing information (current label); EMA. Constella EPAR. PubMed

References are being resolved to PubMed/DOI identifiers; links search PubMed for the citation until then.

† Being confirmed by our reviewers against current sources.

10Community

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Self-reported side effects Phase 2

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11Page history

30 Oct 2026Profile published — awaiting medical review

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