Linaclotide

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
Thumb
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.

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

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.

TargetActionsOrganism
AHeat-stable enterotoxin receptor
agonist
Humans
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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Toxicity

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.
DrugInteraction
AcetazolamideThe risk or severity of adverse effects 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.
AmilorideThe risk or severity of adverse effects can be increased when Amiloride is combined with Linaclotide.
AmiodaroneThe therapeutic efficacy of Linaclotide can be decreased when used in combination with Amiodarone.
AmitriptylineThe therapeutic efficacy of Linaclotide can be decreased when used in combination with Amitriptyline.
AmlodipineThe therapeutic efficacy of Linaclotide can be decreased when used in combination with Amlodipine.
AmobarbitalThe therapeutic efficacy of Linaclotide can be decreased when used in combination with Amobarbital.
Interactions
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Food Interactions
  • Avoid fatty foods. Co-administration with fatty foods may cause loose stools.

Products

Products
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Product Ingredients
IngredientUNIICASInChI Key
Linaclotide acetateNSF067KU1M851199-60-5KWFNVZFWXXEJKL-YZDVLOIKSA-N
Product Images
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ConstellaCapsuleOralAllergan2014-12-17Not applicableCanada flag
ConstellaCapsuleOralAllergan Pharmaceuticals International Limited2016-09-08Not applicableEU flag
ConstellaCapsuleOralAllergan2014-04-29Not applicableCanada flag
ConstellaCapsuleOralAllergan Pharmaceuticals International Limited2016-09-08Not applicableEU flag
ConstellaCapsuleOralAllergan2018-04-02Not applicableCanada flag
ConstellaCapsuleOralAllergan Pharmaceuticals International Limited2016-09-08Not applicableEU flag
ConstellaCapsuleOralAllergan Pharmaceuticals International Limited2016-09-08Not applicableEU flag
LinzessCapsule, gelatin coated145 ug/1OralAvera McKennan Hospital2015-06-042017-05-24US flag69189 120220180907 15195 h7ajiq
LinzessCapsule, gelatin coated290 ug/1OralAllergan, Inc.2012-09-08Not applicableUS flag
LinzessCapsule, gelatin coated145 ug/1OralLake Erie Medical DBA Quality Care Products LLC2012-08-302017-11-02US 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
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[22.22.4.2¹⁶,³³.0⁷,¹¹]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. [PubMed:23090647]
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
AHFS Codes
  • 56:92.00 — Miscellaneous GI Drugs
FDA label
Download (226 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingTreatmentChronic Constipation / Diabete Mellitus1
4CompletedTreatmentChronic idiopathic constipation (CIC) / Constipation-predominant Irritable Bowel Syndrome (IBS-C)1
4CompletedTreatmentCrohn's Disease (CD) / Gastrointestinal Bleeding / Ulcerative Colitis1
4TerminatedTreatmentIrritable Bowel Syndrome Characterized by Constipation1
3CompletedTreatmentChronic Constipation3
3CompletedTreatmentChronic Constipation / Constipation1
3CompletedTreatmentChronic Constipation / Constipation-predominant Irritable Bowel Syndrome (IBS-C)2
3CompletedTreatmentChronic idiopathic constipation (CIC)1
3CompletedTreatmentConstipation-predominant Irritable Bowel Syndrome (IBS-C)2
3CompletedTreatmentIrritable Bowel Syndrome Characterized by Constipation2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral
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
US10675325No2011-08-112031-08-11US flag
US10702576No2011-08-112031-08-11US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilitySlightly soluble FDA
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
Polarizability145.88 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
Not Available

Targets

Drugtargets
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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. [PubMed:23090647]

Drug created on May 30, 2013 06:18 / Updated on May 06, 2021 06:19