Linaclotide

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
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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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Management ofChronic idiopathic constipation•••••••••••••••••
Management ofFunctional constipation (fc)••••••••••••••••••••••• •••••••••
Management ofIrritable bowel syndrome with constipation•••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

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

TargetActionsOrganism
AHeat-stable enterotoxin receptor
agonist
Humans
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

Hover over products below to view reaction partners

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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Toxicity

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.
DrugInteraction
AcetazolamideThe risk or severity of dehydration can be increased when Acetazolamide is combined with Linaclotide.
AclidiniumThe therapeutic efficacy of Linaclotide can be decreased when used in combination with Aclidinium.
AlfentanilThe therapeutic efficacy of Linaclotide can be decreased when used in combination with Alfentanil.
AlloinThe risk or severity of adverse effects can be increased when Linaclotide is combined with Alloin.
AmantadineThe therapeutic efficacy of Linaclotide can be decreased when used in combination with Amantadine.
Food Interactions
  • 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

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Product Ingredients
IngredientUNIICASInChI Key
Linaclotide acetateNSF067KU1M851199-60-5KWFNVZFWXXEJKL-YZDVLOIKSA-N
Product Images
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ConstellaCapsule290 mcgOralAbb Vie Deutschland Gmb H & Co. Kg2016-09-08Not applicableEU flag
ConstellaCapsule72 mcgOralAbbvie2018-04-02Not applicableCanada flag
ConstellaCapsule290 mcgOralAbb Vie Deutschland Gmb H & Co. Kg2016-09-08Not applicableEU flag
ConstellaCapsule290 mcgOralAbbvie2014-12-17Not applicableCanada flag
ConstellaCapsule290 mcgOralAbb Vie Deutschland Gmb H & Co. Kg2016-09-08Not applicableEU flag

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
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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
  1. 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]
  2. Kalola UK, Chowdhury YS: Linaclotide. . [Article]
  3. 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]
  4. 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]
  5. 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]
  6. FDA Approved Drug Products: LINZESS (linaclotide) Oral Capsules (April 2021) [Link]
  7. FDA Approved Drug Products: LINZESS (linaclotide) Oral Capsules (June 2023) [Link]
  8. EMA Approved Drug Products: CONSTELLA (Linaclotide) Oral Capsules [Link]
  9. Health Canada Approved Drug Products: CONSTELLA (Linaclotide) Oral Capsules [Link]
KEGG Drug
D09355
PubChem Compound
16158208
PubChem Substance
175427136
ChemSpider
17314504
RxNav
1307404
ChEBI
68551
ChEMBL
CHEMBL3301675
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Linaclotide

Clinical Trials

Clinical Trials

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral145 mcg
CapsuleOral290 mcg
CapsuleOral290 MICROGRAMMI
CapsuleOral72 mcg
CapsuleOral0.145 mg
Capsule, gelatin coatedOral145 ug/1
Capsule, gelatin coatedOral290 ug/1
Capsule, gelatin coatedOral72 ug/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8110553No2012-02-072024-01-28US flag
US8748573No2014-06-102031-06-20US flag
US7304036No2007-12-042026-08-30US flag
US7704947No2010-04-272024-01-28US flag
US8080526No2011-12-202024-01-28US flag
US8933030No2015-01-132031-02-17US flag
US7371727No2008-05-132024-01-28US flag
US8802628No2014-08-122031-07-24US flag
US7745409No2010-06-292024-01-28US flag
US9708371No2017-07-182033-08-16US flag
US10675325No2020-06-092031-08-11US flag
US10702576No2020-07-072031-08-11US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilitySlightly soluble https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/202811s021lbl.pdf
Predicted Properties
PropertyValueSource
Water Solubility0.701 mg/mLALOGPS
logP-1.5ALOGPS
logP-11Chemaxon
logS-3.3ALOGPS
pKa (Strongest Acidic)3.06Chemaxon
pKa (Strongest Basic)7.65Chemaxon
Physiological Charge-1Chemaxon
Hydrogen Acceptor Count22Chemaxon
Hydrogen Donor Count19Chemaxon
Polar Surface Area573.91 Å2Chemaxon
Rotatable Bond Count13Chemaxon
Refractivity368 m3·mol-1Chemaxon
Polarizability145.19 Å3Chemaxon
Number of Rings6Chemaxon
Bioavailability0Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption-0.6643
Blood Brain Barrier-0.9796
Caco-2 permeable-0.786
P-glycoprotein substrateSubstrate0.7846
P-glycoprotein inhibitor INon-inhibitor0.9096
P-glycoprotein inhibitor IINon-inhibitor0.993
Renal organic cation transporterNon-inhibitor0.8841
CYP450 2C9 substrateNon-substrate0.8072
CYP450 2D6 substrateNon-substrate0.7947
CYP450 3A4 substrateSubstrate0.5121
CYP450 1A2 substrateNon-inhibitor0.9053
CYP450 2C9 inhibitorNon-inhibitor0.8507
CYP450 2D6 inhibitorNon-inhibitor0.8759
CYP450 2C19 inhibitorNon-inhibitor0.8164
CYP450 3A4 inhibitorNon-inhibitor0.8592
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8908
Ames testNon AMES toxic0.6831
CarcinogenicityNon-carcinogens0.7978
BiodegradationNot ready biodegradable0.9839
Rat acute toxicity3.0981 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9284
hERG inhibition (predictor II)Inhibitor0.5115
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-0560-0400290000-c0eb934aef90108b34c4
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-05gi-0100390000-975110a6c7eeb093f970
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0a4i-0008490000-a2cee24d94f4a5169ea5
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-08fr-1004930000-5bce017a918d7462b804
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0a4i-2923220000-af7eb8cacbee4e4bc57a
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-01oy-3147910000-ae2dfddd1c10de30f458
Chromatographic Properties
Collision Cross Sections (CCS)
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
  1. 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]
  2. 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]
  3. FDA Approved Drug Products: LINZESS (linaclotide) Oral Capsules (June 2023) [Link]

Drug created at May 30, 2013 06:18 / Updated at April 09, 2024 18:21