Identification
- Summary
Linaclotide is a guanylate cyclase-C agonist used to treat constipation associated with irritable bowel syndrome or that is idiopathic in nature.
- Brand Names
- Constella, Linzess
- Generic Name
- Linaclotide
- DrugBank Accession Number
- DB08890
- Background
Linaclotide is an orally administered, peptide agonist of guanylate cyclase 2C for the treatment of irritable bowel syndrome. Chemically, it is a heterodetic cyclic peptide and consists of fourteen amino acids. The protein sequence is as follows: Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr. There are three disulfide bonds which are located between Cys1 and Cys6; between Cys2 and Cys10; and between Cys5 and Cys13. FDA approved on August 30, 2012.
- Type
- Small Molecule
- Groups
- Approved
- Structure
Structure for Linaclotide (DB08890)
- Weight
- Average: 1526.736
Monoisotopic: 1525.389918805 - Chemical Formula
- C59H79N15O21S6
- Synonyms
- Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (disulfide bridge: 1-6; 2-10; 5-13)
- Linaclotida
- Linaclotide
- External IDs
- ASP-0456
- ASP0456
- MD-1100
Pharmacology
- Indication
Treatment of irritable bowel syndrome (IBS) with constipation and chronic idiopathic constipation.
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- Contraindications & Blackbox Warnings
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Changes in the appearance and consistency of stools as measured by the Bristol Stool Form Scale (BSFS) have been noted after taking linaclotide.
- Mechanism of action
Linaclotide is an agonist of guanylate cyclase-C (GC-C). Once linaclotide and its active metabolite binds to GC-C, it has local effect on the luminal surface of the intestinal epithelium. Activation of GC-C by linaclotide results in the intra- and extracellular increase of cyclic guanosine monophosphate concentrations (cGMP). This elevation of cGMP levels stimulates the secretion of chloride and bicarbonate into the intestinal lumen via activation of cystic fibrosis transmembrane conductance regulator (CFTR) ion channel. Ultimately, linaclotide helps patients with IBS (especially with constipation) as GI transit is accelerated and the release of intestinal fluid is increased. In animal models, a decrease in visceral pain after administration of linaclotide may be observed. A decrease in the activity of pain-sensing nerves occurs as a result of an increase in extracellular cGMP.
Target Actions Organism AHeat-stable enterotoxin receptor agonistHumans - Absorption
When taken orally, linaclotide is not absorbed into the systemic. No detectable levels of linaclotide or its active metabolite were noted after doses of 125 mcg or 290 mcg were administered.
- Volume of distribution
Given that linaclotide plasma concentrations following therapeutic oral doses are not measurable, linaclotide is expected to be minimally distributed to tissues.
- Protein binding
Not Available
- Metabolism
Linaclotide is metabolized within the gastrointestinal tract to its principal, active metabolite, MM-419447, by loss of the terminal tyrosine moiety. Both linaclotide and the metabolite are proteolytically degraded within the intestinal lumen to smaller peptides and naturally occurring amino acids.
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- Route of elimination
Linaclotide is eliminated fecally (3 - 5% as active metabolites). However most of the dose undergoes proteolysis (processes include reduction of disulfide bonds) in the intestine before being excreted via feces.
- Half-life
Because linaclotide is not systemically absorbed, half life cannot be calculated.
- Clearance
Not Available
- Adverse Effects
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Most common adverse reactions (incidence of at least 2%) reported in IBS-C or CIC patients are diarrhea, abdominal pain, flatulence and abdominal distension.
- 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 adverse effects 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 adverse effects 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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- Avoid fatty foods. Co-administration with fatty foods may cause loose stools.
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 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 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 72 mcg Oral Abbvie 2018-04-02 Not applicable Canada Linzess Capsule, gelatin coated 145 ug/1 Oral Avera McKennan Hospital 2015-06-04 2017-05-24 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 Lake Erie Medical DBA Quality Care Products LLC 2012-08-30 2017-11-02 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]
- FDA Approved Drug Products: LINZESS (linaclotide) 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
- FDA label
- Download (226 KB)
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) / Constipation-predominant Irritable Bowel Syndrome (IBS-C) 1 4 Completed Treatment Crohn's Disease (CD) / Gastrointestinal Hemorrhage / Ulcerative Colitis 1 4 Recruiting Treatment Constipation-predominant Irritable Bowel Syndrome (IBS-C) / Functional Dyspepsia 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 / Constipation-predominant Irritable Bowel Syndrome (IBS-C) 2 3 Completed Treatment Chronic idiopathic constipation (CIC) 1 3 Completed Treatment Constipation-predominant Irritable Bowel Syndrome (IBS-C) 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, 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 FDA - 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
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- 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]
Drug created at May 30, 2013 06:18 / Updated at January 03, 2023 04:22