What it is
Linaclotide is a 14-amino-acid peptide that works as a pill. It is sold as Linzess, a capsule, approved in the US on 30 August 2012. That alone makes it unusual: most peptides are digested in the stomach and gut long before they can act, which is why so many of them are injected.
The Linzess label gives the sequence as Cys-Cys-Glu-Tyr-Cys-Cys-Asn-Pro-Ala-Cys-Thr-Gly-Cys-Tyr. Six of the 14 are cysteines, locked into three disulfide bridges — between positions 1 and 6, 2 and 10, and 5 and 13. That is an unusually dense set of cross-links for a chain this short, and it holds the molecule in a compact fold that protein-cutting enzymes struggle to open. Its molecular weight is 1,526.8.
How it works
Linaclotide's target never requires it to leave the gut. The label describes it as structurally related to guanylin and uroguanylin, the intestine's own hormones, and like them it switches on guanylate cyclase-C (GC-C), a receptor on the inner surface of the intestinal lining. The chain of events, per the label:
- GC-C activation raises cyclic GMP inside and outside the lining cells.
- Cyclic GMP opens the CFTR channel — the same channel that is faulty in cystic fibrosis.
- Chloride and bicarbonate pour into the gut, water follows, and transit speeds up.
The label adds that in an animal model of visceral pain it decreased the activity of pain-sensing nerves by raising cyclic GMP outside the cells — the proposed reason it eases abdominal pain as well as constipation. That part is animal evidence.
In the gut it is trimmed of its final tyrosine into an active metabolite, and both are then broken down to small peptides and amino acids. Neither shows up in the blood: at 72, 145 and 290 mcg, plasma levels were below the limit of quantitation, so the label reports no half-life at all. It is a peptide drug designed never to be absorbed.
The evidence
| Trials (Linzess label) | People | Endpoint | Linaclotide | Placebo |
|---|---|---|---|---|
| IBS-C Trial 1, 290 mcg | 800 | Combined responder, 9 of 12 weeks | 12% | 5% |
| IBS-C Trial 2, 290 mcg | 804 | Combined responder, 9 of 12 weeks | 13% | 3% |
| IBS-C Trial 1 | 800 | Complete-bowel-movement responder | 20% | 6% |
| Chronic constipation, Trials 3 and 4 | 1,272 | Complete-bowel-movement responder, 9 of 12 weeks | reported in the label's table |
The "combined responder" bar is strict — at least 30% less pain and more complete bowel movements in the same week, for 9 of 12 weeks — which is why the absolute rates look low; the difference from placebo was 7 and 10 percentage points. The adult IBS-C trials were 90% women, a limit on how far the figures speak for men. A paediatric IBS-C trial of 53 children reported a 30% combined responder rate over 6 of 12 weeks.
Doses on the label
Reported as the Linzess label states them, not as guidance: IBS-C, adults — 290 mcg once daily; chronic idiopathic constipation, adults — 145 mcg or 72 mcg; IBS-C, children 7 and over — 145 mcg; functional constipation, children 2 and over — 72 mcg. The label directs the capsule be taken on an empty stomach at least 30 minutes before a meal.
Safety
The boxed warning concerns the youngest: linaclotide is contraindicated under age 2, because in neonatal mice a single dose equivalent to an adult's caused deaths from dehydration. It is also contraindicated with known or suspected mechanical bowel obstruction. The commonest effect is diarrhoea, followed by abdominal pain, flatulence and distension; severe diarrhoea is a label warning in its own right.
Where it stands
FDA application data list 72, 145 and 290 mcg capsules as current prescription products (2026-09-28); the label was last revised on 21 May 2026. ClinicalTrials.gov holds 60 records with linaclotide as an intervention; Europe PMC's MEDLINE index holds 440 records naming it, 45 tagged as randomised controlled trials.
Related reading
Linaclotide is the clearest counter-example to the rule that peptides must be injected; another oral peptide in the library is desmopressin, which is absorbed. For a venom peptide with the same count of three disulfide bridges, see ziconotide; for how the bonds between its amino acids form, see the peptide bond entry.