Identification
- Summary
Linaclotide is a guanylate cyclase-C agonist used to treat different types of constipation, such as irritable bowel syndrome-related constipation, idiopathic constipation, and functional constipation.
- Brand Names
- Constella, Linzess
- Generic Name
- Linaclotide
- DrugBank Accession Number
- DB08890
- Background
Linaclotide is a synthetic 14-amino acid cyclic peptide 2 and first-in-class guanylate cyclase-C (G-CC) agonist.2,7 Linaclotide is structurally related to human guanylin and uroguanylin, paracrine peptide hormones that are endogenous activators of GC-C.3 It is also a homolog of a heat-stable enterotoxin derived from Escherichia coli, the first natural ligand that activates GC-C.5
Linaclotide is used for the treatment of various types of constipation, including irritable bowel syndrome with constipation. Linaclotide was first approved by the FDA on August 30, 2012.2 It gained EMA and Health Canada approval on November 26, 2012 8 and December 3, 2013,9 respectively. Linaclotide works to improve the symptoms of constipation and gastrointestinal symptoms of conditions involving constipation.5
- Type
- Small Molecule
- Groups
- Approved
- Structure
Structure for Linaclotide (DB08890)
- Weight
- Average: 1526.736
Monoisotopic: 1525.389918805 - Chemical Formula
- C59H79N15O21S6
- Synonyms
- (9-L-TYROSINE)HEAT-STABLE ENTEROTOXIN (ESCHERICHIA COLI)-(6-19)-PEPTIDE
- L-TYROSINE, L-CYSTEINYL-L-CYSTEINYL-L-.ALPHA.-GLUTAMYL-L-TYROSYL-L-CYSTEINYL-L-CYSTEINYL-L-ASPARAGINYL-L-PROLYL-L-ALANYL-L-CYSTEINYL-L-THREONYLGLYCYL-L-CYSTEINYL-, CYCLIC (1->6),(2->10),(5->13)-TRIS(DISULFIDE)
- Linaclotida
- Linaclotide
- External IDs
- ASP-0456
- ASP0456
- MD-1100
Pharmacology
- Indication
Linaclotide is indicated for the treatment of irritable bowel syndrome with constipation in adults. This indication is approved in the US, Canada, and Europe.7,8,9
In the US and Canada, it is also indicated for the treatment of chronic idiopathic constipation in adults.7,9
In the US, it is also indicated for the treatment of functional constipation in pediatric patients 6 to 17 years of age.7
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- Contraindications & Blackbox Warnings
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Linaclotide is a laxative with visceral analgesic and secretory activities.9 In animal studies and clinical trials, linaclotide improved constipation and gastrointestinal symptoms in patients with irritable bowel syndrome with predominant constipation and chronic idiopathic constipation.2 In animal models, linaclotide has been shown to both accelerate gastrointestinal transit and reduce intestinal pain. In an animal model of visceral pain, linaclotide reduced abdominal muscle contraction and decreased the activity of pain-sensing nerves.7 Taking linaclotide with a high-fat meal results in looser stools and a higher stool frequency than taking it in the fasted state.7
Linaclotide binds to its target, guanylate cyclase-C (GC-C), with high affinity and selectivity. Linaclotide and its active metabolite act locally on the luminal surface of the intestinal epithelium.2,7 As linaclotide is stable under a highly acidic pH environment, it acts in a pH-independent manner.1,2,3
- Mechanism of action
Linaclotide is a potent, highly selective agonist of guanylate cyclase-C (GC-C),7 a soluble and single-membrane-spanning enzyme on the luminal surface of intestinal epithelial cells. GC-C regulates chloride secretion.5 Linaclotide has a dual mode of action. Firstly, linaclotide and its active metabolite bind to transmembrane GC-C. Activation of GC-C results in an increase in both intracellular and extracellular concentrations of cyclic guanosine monophosphate (cGMP). Elevated intracellular cGMP activates the cGMP-dependent protein kinase II (PKG-II), which phosphorylates and activates the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel expressed on the apical surface of intestinal epithelial cells.3 CFTR activation promotes the secretion of chloride and bicarbonate ions and inhibits sodium absorption, resulting in increased intestinal fluid and accelerated GI transit.2,3,7
Secondly, linaclotide exerts anti-nociceptive effects by reducing visceral hypersensitivity. Increased levels of extracellular cGMP in submucosa inhibit colonic nociceptors, relieving intestinal pain.2,3,4
Target Actions Organism AHeat-stable enterotoxin receptor agonistHumans - Absorption
Linaclotide is minimally absorbed with negligible systemic availability following oral administration; however, systemic exposure is not of importance for the maximal effects of linaclotide, as the ligand-binding domain of the GC-C target is located on the luminal surface of intestinal epithelial cells.1 There is no available information regarding the area under the curve (AUC) and peak plasma concentrations (Cmax) as the concentrations of linaclotide and its active metabolite in plasma are below the limit of quantitation.7
- Volume of distribution
Given that linaclotide plasma concentrations following recommended oral doses are not measurable, linaclotide is not expected to be distributed to tissues to any clinically relevant extent.7
- Protein binding
No information is available.
- Metabolism
Linaclotide is metabolized in the small intestine, where it loses its C-terminal tyrosine moiety to form a principal active metabolite, MM-419447.1,4 The disulfide bonds of linaclotide and MM-419447 are reduced in the intestinal lumen, followed by proteolysis and degradation to form smaller peptides and naturally occurring amino acids 1,7 which are absorbed through the intestine.5
In rats in vitro, linaclotide was resistant to enzymatic hydrolysis by pepsin, trypsin, aminopeptidase or chymotrypsin.5
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- Route of elimination
Following once-daily administration of 290 mcg linaclotide for seven days, the average active peptide recovery in the stool samples of fed and fasted healthy subjects was 3% and 5%, respectively. The recovered active peptide constituted the active metabolite.7
- Half-life
There is no available information regarding the half-life as the concentrations of linaclotide and its active metabolite in plasma are below the limit of quantitation.7
- Clearance
No information is available.
- Adverse Effects
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No information is available regarding the LD50 or overdose of linaclotide. Single linaclotide doses of 2897 mcg were administered to 22 healthy subjects; the safety profile in these subjects was consistent with that in the overall linaclotide-treated population, with diarrhea being the most commonly reported adverse reaction.7
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAcetazolamide The risk or severity of dehydration can be increased when Acetazolamide is combined with Linaclotide. Aclidinium The therapeutic efficacy of Linaclotide can be decreased when used in combination with Aclidinium. Alfentanil The therapeutic efficacy of Linaclotide can be decreased when used in combination with Alfentanil. Alloin The risk or severity of adverse effects can be increased when Linaclotide is combined with Alloin. Amantadine The therapeutic efficacy of Linaclotide can be decreased when used in combination with Amantadine. Amiloride The risk or severity of dehydration can be increased when Amiloride is combined with Linaclotide. Amiodarone The therapeutic efficacy of Linaclotide can be decreased when used in combination with Amiodarone. Amitriptyline The therapeutic efficacy of Linaclotide can be decreased when used in combination with Amitriptyline. Amlodipine The therapeutic efficacy of Linaclotide can be decreased when used in combination with Amlodipine. Amobarbital The therapeutic efficacy of Linaclotide can be decreased when used in combination with Amobarbital. 
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- Take on an empty stomach. Take linaclotide at least 30 minutes prior to a meal, at approximately the same time each day. A high fat meal may cause looser stools and a higher stool frequency.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Product Ingredients
Ingredient UNII CAS InChI Key Linaclotide acetate NSF067KU1M 851199-60-5 KWFNVZFWXXEJKL-YZDVLOIKSA-N - Product Images
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Constella Capsule 290 mcg Oral Abb Vie Deutschland Gmb H & Co. Kg 2016-09-08 Not applicable EU 
Constella Capsule 145 mcg Oral Abbvie 2014-04-29 Not applicable Canada 
Constella Capsule 290 mcg Oral Abb Vie Deutschland Gmb H & Co. Kg 2016-09-08 Not applicable EU Constella Capsule 72 mcg Oral Abbvie 2018-04-02 Not applicable Canada Constella Capsule 290 mcg Oral Abb Vie Deutschland Gmb H & Co. Kg 2016-09-08 Not applicable EU Constella Capsule 290 mcg Oral Abbvie 2014-12-17 Not applicable Canada Constella Capsule 290 mcg Oral Abb Vie Deutschland Gmb H & Co. Kg 2016-09-08 Not applicable EU Linzess Capsule, gelatin coated 145 ug/1 Oral Lake Erie Medical DBA Quality Care Products LLC 2012-08-30 2017-11-02 US 
Linzess Capsule, gelatin coated 290 ug/1 Oral Allergan, Inc. 2012-09-08 Not applicable US Linzess Capsule, gelatin coated 145 ug/1 Oral Avera McKennan Hospital 2015-06-04 2017-05-24 US 
Categories
- ATC Codes
- A06AX04 — Linaclotide
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as polypeptides. These are peptides containing ten or more amino acid residues.
- Kingdom
- Organic compounds
- Super Class
- Organic Polymers
- Class
- Polypeptides
- Sub Class
- Not Available
- Direct Parent
- Polypeptides
- Alternative Parents
- Cyclic peptides / Tyrosine and derivatives / Phenylalanine and derivatives / N-acyl-L-alpha-amino acids / Alpha amino acid amides / Phenylpropanoic acids / Amphetamines and derivatives / 1-hydroxy-2-unsubstituted benzenoids / Dicarboxylic acids and derivatives / Tertiary carboxylic acid amides show 14 more
- Substituents
- 1-hydroxy-2-unsubstituted benzenoid / 3-phenylpropanoic-acid / Alcohol / Alpha-amino acid amide / Alpha-amino acid or derivatives / Amine / Amino acid / Amino acid or derivatives / Amphetamine or derivatives / Aromatic heteropolycyclic compound show 33 more
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- heterodetic cyclic peptide (CHEBI:68551)
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- N0TXR0XR5X
- CAS number
- 851199-59-2
- InChI Key
- KXGCNMMJRFDFNR-WDRJZQOASA-N
- InChI
- InChI=1S/C59H79N15O21S6/c1-26-47(82)69-41-25-101-99-22-38-52(87)65-33(13-14-45(80)81)49(84)66-34(16-28-5-9-30(76)10-6-28)50(85)71-40(54(89)72-39(23-97-96-20-32(60)48(83)70-38)53(88)67-35(18-43(61)78)58(93)74-15-3-4-42(74)56(91)63-26)24-100-98-21-37(64-44(79)19-62-57(92)46(27(2)75)73-55(41)90)51(86)68-36(59(94)95)17-29-7-11-31(77)12-8-29/h5-12,26-27,32-42,46,75-77H,3-4,13-25,60H2,1-2H3,(H2,61,78)(H,62,92)(H,63,91)(H,64,79)(H,65,87)(H,66,84)(H,67,88)(H,68,86)(H,69,82)(H,70,83)(H,71,85)(H,72,89)(H,73,90)(H,80,81)(H,94,95)/t26-,27+,32-,33-,34-,35-,36-,37-,38-,39-,40-,41-,42-,46-/m0/s1
- IUPAC Name
- (2S)-2-{[(1R,4S,7S,13S,16R,21R,24R,27S,30S,33R,38R,44S)-21-amino-13-(carbamoylmethyl)-27-(2-carboxyethyl)-44-[(1R)-1-hydroxyethyl]-30-[(4-hydroxyphenyl)methyl]-4-methyl-3,6,12,15,22,25,28,31,40,43,46,51-dodecaoxo-18,19,35,36,48,49-hexathia-2,5,11,14,23,26,29,32,39,42,45,52-dodecaazatetracyclo[22.22.4.2^{16,33}.0^{7,11}]dopentacontan-38-yl]formamido}-3-(4-hydroxyphenyl)propanoic acid
- SMILES
- [H][C@]1(CSSC[C@]2([H])NC(=O)[C@H](CC3=CC=C(O)C=C3)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H]3CSSC[C@H](NC(=O)[C@H](C)NC(=O)[C@@H]4CCCN4C(=O)[C@H](CC(N)=O)NC(=O)[C@H](CSSC[C@H](N)C(=O)N3)NC2=O)C(=O)N[C@@]([H])([C@@H](C)O)C(=O)NCC(=O)N1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O
References
- General References
- Busby RW, Kessler MM, Bartolini WP, Bryant AP, Hannig G, Higgins CS, Solinga RM, Tobin JV, Wakefield JD, Kurtz CB, Currie MG: Pharmacologic properties, metabolism, and disposition of linaclotide, a novel therapeutic peptide approved for the treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation. J Pharmacol Exp Ther. 2013 Jan;344(1):196-206. doi: 10.1124/jpet.112.199430. Epub 2012 Oct 22. [Article]
- Kalola UK, Chowdhury YS: Linaclotide. . [Article]
- Layer P, Stanghellini V: Review article: Linaclotide for the management of irritable bowel syndrome with constipation. Aliment Pharmacol Ther. 2014 Feb;39(4):371-84. doi: 10.1111/apt.12604. Epub 2014 Jan 16. [Article]
- McWilliams V, Whiteside G, McKeage K: Linaclotide: first global approval. Drugs. 2012 Nov 12;72(16):2167-75. doi: 10.2165/11470590-000000000-00000. [Article]
- Corsetti M, Tack J: Linaclotide: A new drug for the treatment of chronic constipation and irritable bowel syndrome with constipation. United European Gastroenterol J. 2013 Feb;1(1):7-20. doi: 10.1177/2050640612474446. [Article]
- FDA Approved Drug Products: LINZESS (linaclotide) Oral Capsules (April 2021) [Link]
- FDA Approved Drug Products: LINZESS (linaclotide) Oral Capsules (June 2023) [Link]
- EMA Approved Drug Products: CONSTELLA (Linaclotide) Oral Capsules [Link]
- Health Canada Approved Drug Products: CONSTELLA (Linaclotide) Oral Capsules [Link]
- External Links
- KEGG Drug
- D09355
- PubChem Compound
- 16158208
- PubChem Substance
- 175427136
- ChemSpider
- 17314504
- 1307404
- ChEBI
- 68551
- ChEMBL
- CHEMBL3301675
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Linaclotide
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 4 Active Not Recruiting Treatment Chronic Constipation / Diabetes Mellitus 1 4 Completed Treatment Chronic idiopathic constipation (CIC) / Irritable Bowel Syndrome With Constipation (IBS-C) 1 4 Completed Treatment Crohn's Disease (CD) / Gastrointestinal Hemorrhage / Ulcerative Colitis 1 4 Recruiting Treatment Functional Dyspepsia / Irritable Bowel Syndrome With Constipation (IBS-C) 1 4 Terminated Treatment Irritable Bowel Syndrome Characterized by Constipation 1 3 Completed Treatment Chronic Constipation 3 3 Completed Treatment Chronic Constipation / Constipation 1 3 Completed Treatment Chronic Constipation / Irritable Bowel Syndrome With Constipation (IBS-C) 2 3 Completed Treatment Chronic idiopathic constipation (CIC) 1 3 Completed Treatment Irritable Bowel Syndrome Characterized by Constipation 2
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Capsule Oral 145 mcg Capsule Oral 290 MICROGRAMMI Capsule Oral 290 mcg Capsule Oral 72 mcg Capsule Oral 0.145 mg Capsule, gelatin coated Oral 145 ug/1 Capsule, gelatin coated Oral 290 ug/1 Capsule, gelatin coated Oral 72 ug/1 - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US8110553 No 2012-02-07 2024-01-28 US US8748573 No 2014-06-10 2031-06-20 US US7304036 No 2007-12-04 2026-08-30 US US7704947 No 2010-04-27 2024-01-28 US US8080526 No 2011-12-20 2024-01-28 US US8933030 No 2015-01-13 2031-02-17 US US7371727 No 2008-05-13 2024-01-28 US US8802628 No 2014-08-12 2031-07-24 US US7745409 No 2010-06-29 2024-01-28 US US9708371 No 2017-07-18 2033-08-16 US US10675325 No 2020-06-09 2031-08-11 US US10702576 No 2020-07-07 2031-08-11 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source water solubility Slightly soluble https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/202811s021lbl.pdf - Predicted Properties
Property Value Source Water Solubility 0.701 mg/mL ALOGPS logP -1.5 ALOGPS logP -11 Chemaxon logS -3.3 ALOGPS pKa (Strongest Acidic) 3.06 Chemaxon pKa (Strongest Basic) 7.65 Chemaxon Physiological Charge -1 Chemaxon Hydrogen Acceptor Count 22 Chemaxon Hydrogen Donor Count 19 Chemaxon Polar Surface Area 573.91 Å2 Chemaxon Rotatable Bond Count 13 Chemaxon Refractivity 368 m3·mol-1 Chemaxon Polarizability 145.19 Å3 Chemaxon Number of Rings 6 Chemaxon Bioavailability 0 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption - 0.6643 Blood Brain Barrier - 0.9796 Caco-2 permeable - 0.786 P-glycoprotein substrate Substrate 0.7846 P-glycoprotein inhibitor I Non-inhibitor 0.9096 P-glycoprotein inhibitor II Non-inhibitor 0.993 Renal organic cation transporter Non-inhibitor 0.8841 CYP450 2C9 substrate Non-substrate 0.8072 CYP450 2D6 substrate Non-substrate 0.7947 CYP450 3A4 substrate Substrate 0.5121 CYP450 1A2 substrate Non-inhibitor 0.9053 CYP450 2C9 inhibitor Non-inhibitor 0.8507 CYP450 2D6 inhibitor Non-inhibitor 0.8759 CYP450 2C19 inhibitor Non-inhibitor 0.8164 CYP450 3A4 inhibitor Non-inhibitor 0.8592 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.8908 Ames test Non AMES toxic 0.6831 Carcinogenicity Non-carcinogens 0.7978 Biodegradation Not ready biodegradable 0.9839 Rat acute toxicity 3.0981 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.9284 hERG inhibition (predictor II) Inhibitor 0.5115
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Not Available
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Agonist
- General Function
- Toxic substance binding
- Specific Function
- Receptor for the E.coli heat-stable enterotoxin (E.coli enterotoxin markedly stimulates the accumulation of cGMP in mammalian cells expressing GC-C). Also activated by the endogenous peptides guany...
- Gene Name
- GUCY2C
- Uniprot ID
- P25092
- Uniprot Name
- Heat-stable enterotoxin receptor
- Molecular Weight
- 123401.73 Da
References
- Busby RW, Kessler MM, Bartolini WP, Bryant AP, Hannig G, Higgins CS, Solinga RM, Tobin JV, Wakefield JD, Kurtz CB, Currie MG: Pharmacologic properties, metabolism, and disposition of linaclotide, a novel therapeutic peptide approved for the treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation. J Pharmacol Exp Ther. 2013 Jan;344(1):196-206. doi: 10.1124/jpet.112.199430. Epub 2012 Oct 22. [Article]
- Layer P, Stanghellini V: Review article: Linaclotide for the management of irritable bowel syndrome with constipation. Aliment Pharmacol Ther. 2014 Feb;39(4):371-84. doi: 10.1111/apt.12604. Epub 2014 Jan 16. [Article]
- FDA Approved Drug Products: LINZESS (linaclotide) Oral Capsules (June 2023) [Link]
Drug created at May 30, 2013 06:18 / Updated at October 02, 2023 22:11