Identification

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Name
Eluxadoline
Accession Number
DB09272
Type
Small Molecule
Groups
Approved, Investigational
Description

Eluxadoline is a mixed mu-opioid receptor agonist, kappa-opioid receptor agonist, and a-delta opioid receptor antagonist indicated for use in diarrhea-predominant irritable bowel syndrome (IBS-D). The mu-, kappa-, and delta-opioid receptors mediate endogenous and exogenous opioid response in the central nervous system and peripherally in the gastrointestinal system. Agonism of peripheral mu-opioid receptors results in reduced colonic motility, while antagonism of central delta-opioid receptors results in improved analgesia, making eluxadoline usable for the symptoms of both pain and diarrhea characteristic of IBS-D.

Marketed under the tradename Viberzi (FDA), eluxadoline is an antimotility agent that decreases bowel contractions, inhibits colonic transit, and reduces fluid/ion secretion resulting in improved symptoms of abdominal pain and reductions in the Bristol Stool Scale.

Structure
Thumb
Synonyms
  • 5-({(4-carbamoyl-2,6-dimethyl-L-phenylalanyl)[(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino}methyl)-2-methoxybenzoic acid
  • Eluxadoline
External IDs
JNJ 27018966 / JNJ-27018966 / JNJ27018966
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
ViberziTablet, film coated100 mg/1OralAllergan, Inc.2015-10-01Not applicableUs
ViberziTablet, film coated75 mg/1OralAllergan, Inc.2015-10-01Not applicableUs
ViberziTablet100 mgOralAllergan Pharma Co.2017-04-24Not applicableCanada
ViberziTablet75 mgOralAllergan Pharma Co.2017-04-24Not applicableCanada
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories
UNII
45TPJ4MBQ1
CAS number
864821-90-9
Weight
Average: 569.662
Monoisotopic: 569.263819247
Chemical Formula
C32H35N5O5
InChI Key
QFNHIDANIVGXPE-FNZWTVRRSA-N
InChI
InChI=1S/C32H35N5O5/c1-18-12-23(29(34)38)13-19(2)24(18)15-26(33)31(39)37(17-21-10-11-28(42-4)25(14-21)32(40)41)20(3)30-35-16-27(36-30)22-8-6-5-7-9-22/h5-14,16,20,26H,15,17,33H2,1-4H3,(H2,34,38)(H,35,36)(H,40,41)/t20-,26-/m0/s1
IUPAC Name
5-{[(2S)-2-amino-3-(4-carbamoyl-2,6-dimethylphenyl)-N-[(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]propanamido]methyl}-2-methoxybenzoic acid
SMILES
COC1=CC=C(CN([C@@H](C)C2=NC(=CN2)C2=CC=CC=C2)C(=O)[C@@H](N)CC2=C(C)C=C(C=C2C)C(N)=O)C=C1C(O)=O

Pharmacology

Indication

For the treatment of irritable bowel syndrome with diarrhea (IBS-D).

Associated Conditions
Pharmacodynamics
Not Available
Mechanism of action

Eluxadoline is a mu-opioid receptor agonis, kappa opioid receptor agonist and a delta opioid receptor antagonist. Eluxadoline is used for diarrhea predominant IBS because it reduces intestinal contractility and normalizes stress-induced acceleration of upper GI transit. Antagonistic activity at the delta receptor minimizes the constipating effect usually seen by mu-opioid receptor agonists alone. Because of it's limited systemic bioavailability, there may be less side effects associated with the use of eluxadoline in comparison with other therapies used to treat diarrhea predominant IBS.

TargetActionsOrganism
AMu-type opioid receptor
agonist
Humans
ADelta-type opioid receptor
antagonist
Humans
AKappa-type opioid receptor
agonist
Humans
Additional Data Available
Adverse Effects

Comprehensive structured data on known drug adverse effects with statistical prevalence. MedDRA and ICD10 ids are provided for adverse effect conditions and symptoms.

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Additional Data Available
Contraindications

Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.

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Additional Data Available
Blackbox Warnings

Structured data representing warnings from the black box section of drug labels. These warnings cover important and dangerous risks, contraindications, or adverse effects.

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Absorption

The oral absorption of eluxadoline is poor - estimated to be 1.02%, this could be attributed to poor in vitro GI permeability, and its zwitterionic nature leading to a negatively charged molecule across the GI pH range.

Volume of distribution
Not Available
Protein binding

81%

Metabolism

The metabolism of eluxadoline is currently unclear, however evidence suggests limited glucoronidation forms an acyl glucuronide metabolite that is then excreted into urine.

Route of elimination

82% excreted in feces, <1% excreted in urine.

Half life

The mean plasma elimination half-life ranged from 3.7 hours to 6 hours.

Clearance
Not Available
Toxicity

The most common adverse reactions (>5%) are constipation, nausea and abdominal pain.

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
2,5-Dimethoxy-4-ethylamphetamine2,5-Dimethoxy-4-ethylamphetamine may increase the analgesic activities of Eluxadoline.
2,5-Dimethoxy-4-ethylthioamphetamine2,5-Dimethoxy-4-ethylthioamphetamine may increase the analgesic activities of Eluxadoline.
4-Bromo-2,5-dimethoxyamphetamine4-Bromo-2,5-dimethoxyamphetamine may increase the analgesic activities of Eluxadoline.
5-methoxy-N,N-dimethyltryptamineThe risk or severity of serotonin syndrome can be increased when Eluxadoline is combined with 5-methoxy-N,N-dimethyltryptamine.
7,8-Dichloro-1,2,3,4-tetrahydroisoquinolineThe risk or severity of serotonin syndrome can be increased when 7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline is combined with Eluxadoline.
AcepromazineThe risk or severity of hypotension and CNS depression can be increased when Acepromazine is combined with Eluxadoline.
AceprometazineThe risk or severity of hypotension and CNS depression can be increased when Aceprometazine is combined with Eluxadoline.
AcetazolamideThe therapeutic efficacy of Acetazolamide can be decreased when used in combination with Eluxadoline.
AcetophenazineThe risk or severity of hypotension and CNS depression can be increased when Acetophenazine is combined with Eluxadoline.
AcetylcysteineThe serum concentration of Eluxadoline can be increased when it is combined with Acetylcysteine.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

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Food Interactions
Not Available

References

Synthesis Reference

Breslin HJ, Diamond CJ, Kavash RW, Cai C, Dyatkin AB, Miskowski TA, Zhang SP, Wade PR, Hornby PJ, He W: Identification of a dual delta OR antagonist/mu OR agonist as a potential therapeutic for diarrhea-predominant Irritable Bowel Syndrome (IBS-d). Bioorg Med Chem Lett. 2012 Jul 15;22(14):4869-72. doi: 10.1016/j.bmcl.2012.05.042. Epub 2012 May 24. Pubmed

General References
  1. Garnock-Jones KP: Eluxadoline: First Global Approval. Drugs. 2015 Jul;75(11):1305-10. doi: 10.1007/s40265-015-0436-4. [PubMed:26149369]
  2. Nee J, Zakari M, Lembo AJ: Current and emerging drug options in the treatment of diarrhea predominant irritable bowel syndrome. Expert Opin Pharmacother. 2015 Dec;16(18):2781-92. doi: 10.1517/14656566.2015.1101449. Epub 2015 Nov 11. [PubMed:26558923]
  3. Dove LS, Lembo A, Randall CW, Fogel R, Andrae D, Davenport JM, McIntyre G, Almenoff JS, Covington PS: Eluxadoline benefits patients with irritable bowel syndrome with diarrhea in a phase 2 study. Gastroenterology. 2013 Aug;145(2):329-38.e1. doi: 10.1053/j.gastro.2013.04.006. Epub 2013 Apr 9. [PubMed:23583433]
  4. Davenport JM, Covington P, Bonifacio L, McIntyre G, Venitz J: Effect of uptake transporters OAT3 and OATP1B1 and efflux transporter MRP2 on the pharmacokinetics of eluxadoline. J Clin Pharmacol. 2015 May;55(5):534-42. doi: 10.1002/jcph.442. Epub 2015 Jan 14. [PubMed:25491493]
  5. Fujita W, Gomes I, Dove LS, Prohaska D, McIntyre G, Devi LA: Molecular characterization of eluxadoline as a potential ligand targeting mu-delta opioid receptor heteromers. Biochem Pharmacol. 2014 Dec 1;92(3):448-56. doi: 10.1016/j.bcp.2014.09.015. Epub 2014 Sep 28. [PubMed:25261794]
External Links
KEGG Drug
D10403
PubChem Compound
11250029
PubChem Substance
310265167
ChemSpider
9425062
BindingDB
50393720
ChEBI
85980
ChEMBL
CHEMBL2159122
Wikipedia
Eluxadoline
ATC Codes
A07DA06 — Eluxadoline
AHFS Codes
  • 56:92.00 — Miscellaneous GI Drugs
FDA label
Download (503 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedTreatmentIrritable Bowel Syndrome (IBS)1
2Not Yet RecruitingTreatmentAccidental Bowel Leakage / Anal Incontinence / Incontinence, Fecal / Severe or persistent diarrhea / Urge Incontinence1
2RecruitingTreatmentIrritable Bowel Syndrome (IBS)1
3CompletedTreatmentIrritable Bowel Syndrome (IBS)2
4Active Not RecruitingTreatmentDiarrhoea Predominant Irritable Bowel Syndrome1
4CompletedTreatmentDiarrhoea Predominant Irritable Bowel Syndrome1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral100 mg
TabletOral75 mg
Tablet, film coatedOral100 mg/1
Tablet, film coatedOral75 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US9115091No2015-08-252028-07-07Us
US9205076No2015-12-082025-03-14Us
US8691860No2014-04-082028-07-07Us
US8344011No2013-01-012025-03-14Us
US8609709No2013-12-172025-03-14Us
US7741356No2010-06-222028-03-25Us
US7786158No2010-08-312025-03-14Us
US9364489No2016-06-142028-07-07Us
US8772325No2014-07-082025-03-14Us
US9675587No2017-06-132033-03-14Us
US9700542No2017-07-112025-03-14Us
US9789125No2017-10-172028-07-07Us
US10188632No2019-01-292033-03-14Us
US10213415No2019-02-262025-03-14Us
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

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Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00268 mg/mLALOGPS
logP1.08ALOGPS
logP1.8ChemAxon
logS-5.3ALOGPS
pKa (Strongest Acidic)3.66ChemAxon
pKa (Strongest Basic)7.99ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count4ChemAxon
Polar Surface Area164.63 Å2ChemAxon
Rotatable Bond Count11ChemAxon
Refractivity160.38 m3·mol-1ChemAxon
Polarizability61.86 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as phenylalanine and derivatives. These are compounds containing phenylalanine or a derivative thereof resulting from reaction of phenylalanine at the amino group or the carboxy group, or from the replacement of any hydrogen of glycine by a heteroatom.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
Phenylalanine and derivatives
Alternative Parents
Alpha amino acid amides / Phenylimidazoles / O-methoxybenzoic acids and derivatives / Amphetamines and derivatives / Benzamides / Benzoic acids / m-Xylenes / Benzoyl derivatives / Anisoles / Imidazolyl carboxylic acids and derivatives
show 16 more
Substituents
Phenylalanine or derivatives / Alpha-amino acid amide / O-methoxybenzoic acid or derivatives / 5-phenylimidazole / 4-phenylimidazole / Amphetamine or derivatives / Benzoic acid / Benzoic acid or derivatives / Benzamide / Imidazolyl carboxylic acid derivative
show 35 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
amino acid amide, imidazoles, benzamides, L-phenylalanine derivative, methoxybenzoic acid (CHEBI:85980)

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Voltage-gated calcium channel activity
Specific Function
Receptor for endogenous opioids such as beta-endorphin and endomorphin. Receptor for natural and synthetic opioids including morphine, heroin, DAMGO, fentanyl, etorphine, buprenorphin and methadone...
Gene Name
OPRM1
Uniprot ID
P35372
Uniprot Name
Mu-type opioid receptor
Molecular Weight
44778.855 Da
References
  1. Fujita W, Gomes I, Dove LS, Prohaska D, McIntyre G, Devi LA: Molecular characterization of eluxadoline as a potential ligand targeting mu-delta opioid receptor heteromers. Biochem Pharmacol. 2014 Dec 1;92(3):448-56. doi: 10.1016/j.bcp.2014.09.015. Epub 2014 Sep 28. [PubMed:25261794]
  2. Dove LS, Lembo A, Randall CW, Fogel R, Andrae D, Davenport JM, McIntyre G, Almenoff JS, Covington PS: Eluxadoline benefits patients with irritable bowel syndrome with diarrhea in a phase 2 study. Gastroenterology. 2013 Aug;145(2):329-38.e1. doi: 10.1053/j.gastro.2013.04.006. Epub 2013 Apr 9. [PubMed:23583433]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Opioid receptor activity
Specific Function
G-protein coupled receptor that functions as receptor for endogenous enkephalins and for a subset of other opioids. Ligand binding causes a conformation change that triggers signaling via guanine n...
Gene Name
OPRD1
Uniprot ID
P41143
Uniprot Name
Delta-type opioid receptor
Molecular Weight
40368.235 Da
References
  1. Fujita W, Gomes I, Dove LS, Prohaska D, McIntyre G, Devi LA: Molecular characterization of eluxadoline as a potential ligand targeting mu-delta opioid receptor heteromers. Biochem Pharmacol. 2014 Dec 1;92(3):448-56. doi: 10.1016/j.bcp.2014.09.015. Epub 2014 Sep 28. [PubMed:25261794]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Opioid receptor activity
Specific Function
G-protein coupled opioid receptor that functions as receptor for endogenous alpha-neoendorphins and dynorphins, but has low affinity for beta-endorphins. Also functions as receptor for various synt...
Gene Name
OPRK1
Uniprot ID
P41145
Uniprot Name
Kappa-type opioid receptor
Molecular Weight
42644.665 Da

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostagland...
Gene Name
SLCO1B1
Uniprot ID
Q9Y6L6
Uniprot Name
Solute carrier organic anion transporter family member 1B1
Molecular Weight
76447.99 Da
References
  1. Davenport JM, Covington P, Bonifacio L, McIntyre G, Venitz J: Effect of uptake transporters OAT3 and OATP1B1 and efflux transporter MRP2 on the pharmacokinetics of eluxadoline. J Clin Pharmacol. 2015 May;55(5):534-42. doi: 10.1002/jcph.442. Epub 2015 Jan 14. [PubMed:25491493]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Organic anion transmembrane transporter activity
Specific Function
Mediates hepatobiliary excretion of numerous organic anions. May function as a cellular cisplatin transporter.
Gene Name
ABCC2
Uniprot ID
Q92887
Uniprot Name
Canalicular multispecific organic anion transporter 1
Molecular Weight
174205.64 Da
References
  1. Davenport JM, Covington P, Bonifacio L, McIntyre G, Venitz J: Effect of uptake transporters OAT3 and OATP1B1 and efflux transporter MRP2 on the pharmacokinetics of eluxadoline. J Clin Pharmacol. 2015 May;55(5):534-42. doi: 10.1002/jcph.442. Epub 2015 Jan 14. [PubMed:25491493]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Plays an important role in the excretion/detoxification of endogenous and exogenous organic anions, especially from the brain and kidney. Involved in the transport basolateral of steviol, fexofenad...
Gene Name
SLC22A8
Uniprot ID
Q8TCC7
Uniprot Name
Solute carrier family 22 member 8
Molecular Weight
59855.585 Da
References
  1. Davenport JM, Covington P, Bonifacio L, McIntyre G, Venitz J: Effect of uptake transporters OAT3 and OATP1B1 and efflux transporter MRP2 on the pharmacokinetics of eluxadoline. J Clin Pharmacol. 2015 May;55(5):534-42. doi: 10.1002/jcph.442. Epub 2015 Jan 14. [PubMed:25491493]

Drug created on October 28, 2015 13:50 / Updated on July 15, 2019 20:11