Identification

Summary

Methylnaltrexone is a μ-opioid antagonist used for the treatment of opioid-induced constipation in palliative patients that are inadequately responding to laxative therapy.

Brand Names
Relistor
Generic Name
Methylnaltrexone
DrugBank Accession Number
DB06800
Background

Methylnaltrexone is a pheriphally-acting μ-opioid antagonist that acts on the gastrointestinal tract to decrease opioid-induced constipation without producing analgesic effects or withdrawal symptoms. It is also a weak CYP2D6 inhibitor. FDA approved in 2008.

Type
Small Molecule
Groups
Approved
Structure
Thumb
Weight
Average: 356.441
Monoisotopic: 356.185634741
Chemical Formula
C21H26NO4
Synonyms
  • MNTX
External IDs
  • MRZ 2663BR
  • MRZ-2663

Pharmacology

Indication

Treatment of opioids induced constipation in palliative patients that are inadequately responding to laxative therapy.

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Use of opioids induces slowing of gastrointestinal motility and transit. Following remifentanil administration, the methylnaltrexone and placebo groups showed no change in pupiliary constriction while the naloxone group showed a marked change over the time interval tested.

Mechanism of action

Methylnaltrexone is a pheriphally-acting μ-opioid antagonists that acts on the gastrointestinal tract inhibit opioid-induced decrease in gastric motility and transit time. Because methylnaltrexone is a quaternary derivative of naltrexone, it produces its gastrointestinal effects without producing analgesic effects or withdrawal symptoms as it does not cross the blood-brain-barrier.

TargetActionsOrganism
AMu-type opioid receptor
antagonist
Humans
NKappa-type opioid receptor
antagonist
Humans
Absorption

Methylnaltrexone is rapidly absorbed. Tmax (SubQ): 30 minutes (regardless of dose); Cmax, 0.15 mg/kg SubQ dose = 117 ng/mL; AUC24, 0.15 mg/kg SubQ dose = 175 ng·hr/mL;

Volume of distribution

Volume of distribution, steady state = 1.1 L/kg

Protein binding

11% to 15% bound to human plasma proteins.

Metabolism

60% of the dose is metabolized. Conversion to methyl-6-naltrexol isomers (5% of total dose) and methylnaltrexone sulfate (1.3% of total dose) appear to be the primary pathways of metabolism. N‑demethylation of methylnaltrexone to produce naltrexone is not significant.

Route of elimination

Most of the drug is eliminated as unchanged drug (85% of administered radioactivity). Approximately half of the dose is excreted in the urine and somewhat less in feces.

Half-life

terminal: 8.89 ± 2.59 h (intravenous) terminal: 6.14- 8.83 h (subcutaneous)

Clearance

10.5 ± 1.5 ml/min/kg (IV)

Adverse Effects
Adverseeffects
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Toxicity

LD50: 50 mg/kg (primates); Orthostatic hypotension at plasma levels in excess of 1.400 ng/mL. The most common (>5%) adverse reactions reported with methylnaltrexone bromide are abdominal pain, flatulence, nausea, dizziness, diarrhea and hyperhidrosis.

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
AbacavirAbacavir may decrease the excretion rate of Methylnaltrexone which could result in a higher serum level.
AceclofenacAceclofenac may decrease the excretion rate of Methylnaltrexone which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Methylnaltrexone which could result in a higher serum level.
AcetaminophenAcetaminophen may decrease the excretion rate of Methylnaltrexone which could result in a higher serum level.
AcetazolamideAcetazolamide may increase the excretion rate of Methylnaltrexone which could result in a lower serum level and potentially a reduction in efficacy.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Methylnaltrexone which could result in a higher serum level.
AclidiniumMethylnaltrexone may decrease the excretion rate of Aclidinium which could result in a higher serum level.
AcrivastineMethylnaltrexone may decrease the excretion rate of Acrivastine which could result in a higher serum level.
AcyclovirAcyclovir may decrease the excretion rate of Methylnaltrexone which could result in a higher serum level.
Adefovir dipivoxilAdefovir dipivoxil may decrease the excretion rate of Methylnaltrexone which could result in a higher serum level.
Interactions
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Food Interactions
  • Take on an empty stomach. Take methylnaltrexone at least 30 minutes before breakfast.

Products

Products2
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Product Ingredients
IngredientUNIICASInChI Key
Methylnaltrexone bromideRFO6IL3D3M916055-92-0IFGIYSGOEZJNBE-NQMNLMSRSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
RelistorInjection, solution8 mgSubcutaneousBausch Health Ireland Limited2016-09-08Not applicableEU flag
RelistorInjection, solution12 mg/0.6mLSubcutaneousWyeth Pharmaceuticals Inc., a subsidiary of Pfizer Inc.2008-08-012011-06-30US flag
RelistorSolution20 mg / mLSubcutaneousSalix Pharmaceuticals2008-05-07Not applicableCanada flag
RelistorInjection, solution12 mgSubcutaneousBausch Health Ireland Limited2016-09-08Not applicableEU flag
RelistorInjection, solution12 mg/0.6mlSubcutaneousBausch Health Ireland Limited2016-09-08Not applicableEU flag
RelistorInjection, solution12 mg/0.6mLSubcutaneousSalix Pharmaceuticals, Inc.2010-10-012011-10-18US flag
RelistorInjection, solution8 mgSubcutaneousBausch Health Ireland Limited2016-09-08Not applicableEU flag
RelistorSolution20 mg / mLSubcutaneousSalix PharmaceuticalsNot applicableNot applicableCanada flag
RelistorInjection, solution12 mgSubcutaneousBausch Health Ireland Limited2016-09-08Not applicableEU flag
RelistorInjection, solution12 mg/0.6mlSubcutaneousBausch Health Ireland Limited2016-09-08Not applicableEU flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
RelistorInjection, solution8 mg/0.4mLSubcutaneousSalix Pharmaceuticals, Inc.2008-04-24Not applicableUS flag
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
RelistorMethylnaltrexone bromide (12 mg/0.6mL) + Isopropyl alcohol (0.42 mL/1mL)KitSubcutaneous; TopicalWyeth Pharmaceuticals Inc., a subsidiary of Pfizer Inc.2008-08-012011-06-30US flag
RelistorMethylnaltrexone bromide (12 mg/0.6mL) + Isopropyl alcohol (0.42 mL/1)KitSubcutaneous; TopicalSalix Pharmaceuticals, Inc.2008-08-012011-10-18US flag

Categories

ATC Codes
A06AH01 — Methylnaltrexone bromide
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as phenanthrenes and derivatives. These are polycyclic compounds containing a phenanthrene moiety, which is a tricyclic aromatic compound with three non-linearly fused benzene.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Phenanthrenes and derivatives
Sub Class
Not Available
Direct Parent
Phenanthrenes and derivatives
Alternative Parents
Isoquinolones and derivatives / Tetralins / Coumarans / 1-hydroxy-2-unsubstituted benzenoids / Alkyl aryl ethers / Aralkylamines / Piperidines / Tetraalkylammonium salts / Tertiary alcohols / 1,2-aminoalcohols
show 9 more
Substituents
1,2-aminoalcohol / 1-hydroxy-2-unsubstituted benzenoid / Alcohol / Alkyl aryl ether / Amine / Aralkylamine / Aromatic heteropolycyclic compound / Azacycle / Carbonyl group / Coumaran
show 21 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
0RK7M7IABE
CAS number
916055-93-1
InChI Key
JVLBPIPGETUEET-WIXLDOGYSA-O
InChI
InChI=1S/C21H25NO4/c1-22(11-12-2-3-12)9-8-20-17-13-4-5-14(23)18(17)26-19(20)15(24)6-7-21(20,25)16(22)10-13/h4-5,12,16,19,25H,2-3,6-11H2,1H3/p+1/t16-,19+,20+,21-,22-/m1/s1
IUPAC Name
(1S,4R,5R,13R,17S)-4-(cyclopropylmethyl)-10,17-dihydroxy-4-methyl-14-oxo-12-oxa-4-azapentacyclo[9.6.1.0¹,¹³.0⁵,¹⁷.0⁷,¹⁸]octadeca-7(18),8,10-trien-4-ium
SMILES
C[N@+]1(CC2CC2)CC[C@]23[C@H]4OC5=C(O)C=CC(C[C@@H]1[C@]2(O)CCC4=O)=C35

References

Synthesis Reference

Harold Doshan, Julio Perez, "Synthesis of R-N-methylnaltrexone." U.S. Patent US20070099946, issued May 03, 2007.

US20070099946
General References
  1. Thomas J: Opioid-induced bowel dysfunction. J Pain Symptom Manage. 2008 Jan;35(1):103-13. Epub 2007 Nov 5. [Article]
  2. Rotshteyn Y, Boyd TA, Yuan CS: Methylnaltrexone bromide: research update of pharmacokinetics following parenteral administration. Expert Opin Drug Metab Toxicol. 2011 Feb;7(2):227-35. doi: 10.1517/17425255.2011.549824. Epub 2011 Jan 11. [Article]
  3. Chandrasekaran A, Tong Z, Li H, Erve JC, DeMaio W, Goljer I, McConnell O, Rotshteyn Y, Hultin T, Talaat R, Scatina J: Metabolism of intravenous methylnaltrexone in mice, rats, dogs, and humans. Drug Metab Dispos. 2010 Apr;38(4):606-16. doi: 10.1124/dmd.109.031179. Epub 2010 Jan 6. [Article]
  4. Bader S, Jaroslawski K, Blum HE, Becker G: Opioid-induced constipation in advanced illness: safety and efficacy of methylnaltrexone bromide. Clin Med Insights Oncol. 2011;5:201-11. doi: 10.4137/CMO.S4867. Epub 2011 Jul 14. [Article]
KEGG Drug
D06618
PubChem Compound
16089915
PubChem Substance
175427092
ChemSpider
17248532
RxNav
29899
ChEMBL
CHEMBL1186579
ZINC
ZINC000245204949
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Methylnaltrexone
FDA label
Download (4.17 MB)
MSDS
Download (479 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentConstipation1
4CompletedTreatmentCoronary Artery Disease (CAD)1
4CompletedTreatmentEsophageal Dysfunction / Pharyngeal Dysfunction1
4CompletedTreatmentGastric Motility Disorder1
4CompletedTreatmentMethylnaltrexone / Morphine / ST Segment Elevation Myocardial Infarction (STEMI) / Ticagrelor1
4CompletedTreatmentOpioid Induced Constipation (OIC)2
4RecruitingTreatmentDrug Induced Constipation1
4TerminatedPreventionConstipation1
4Unknown StatusBasic SciencePharyngeal Dysfunction / Pharyngeal Swallowing1
4WithdrawnTreatmentColonic Inertia1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solutionSubcutaneous12 mg
Injection, solutionSubcutaneous12 mg/0.6mL
Injection, solutionSubcutaneous8 mg/0.4mL
Injection, solutionSubcutaneous8 mg
KitSubcutaneous; Topical
SolutionSubcutaneous20 mg / mL
TabletOral150 mg/1
SolutionSubcutaneous12 mg/0.6ml
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8247425No2012-08-212030-12-31US flag
US8420663No2013-04-162029-09-30US flag
US8822490No2014-09-022029-09-30US flag
US9180125No2015-11-102029-09-30US flag
US8552025No2013-10-082024-04-08US flag
US6559158No2003-05-062017-11-03US flag
US9669096No2017-06-062024-04-08US flag
US9314461No2016-04-192031-03-10US flag
US8956651No2015-02-172031-03-10US flag
US8524276No2013-09-032031-03-10US flag
US9724343No2017-08-082029-09-30US flag
US9492445No2016-11-152029-09-30US flag
US10307417No2019-06-042031-03-10US flag
US10376584No2019-08-132024-04-08US flag
US10376505No2019-08-132031-03-10US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubility≥5 mg/mL MSDS
logP2.200MSDS
Predicted Properties
PropertyValueSource
Water Solubility0.00729 mg/mLALOGPS
logP0.59ALOGPS
logP-2.5ChemAxon
logS-4.7ALOGPS
pKa (Strongest Acidic)9.9ChemAxon
pKa (Strongest Basic)-3.9ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area66.76 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity107.42 m3·mol-1ChemAxon
Polarizability38.04 Å3ChemAxon
Number of Rings6ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption-0.8138
Blood Brain Barrier+0.9268
Caco-2 permeable+0.6681
P-glycoprotein substrateSubstrate0.9279
P-glycoprotein inhibitor INon-inhibitor0.9775
P-glycoprotein inhibitor IINon-inhibitor0.943
Renal organic cation transporterNon-inhibitor0.5377
CYP450 2C9 substrateNon-substrate0.7889
CYP450 2D6 substrateSubstrate0.6417
CYP450 3A4 substrateSubstrate0.6999
CYP450 1A2 substrateNon-inhibitor0.8884
CYP450 2C9 inhibitorNon-inhibitor0.9271
CYP450 2D6 inhibitorNon-inhibitor0.6213
CYP450 2C19 inhibitorNon-inhibitor0.8552
CYP450 3A4 inhibitorNon-inhibitor0.9521
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9803
Ames testNon AMES toxic0.6301
CarcinogenicityNon-carcinogens0.9561
BiodegradationNot ready biodegradable0.9528
Rat acute toxicity2.9409 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8578
hERG inhibition (predictor II)Non-inhibitor0.9042
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 GC-MS Spectrum - GC-MSPredicted GC-MSNot Available

Targets

Drugtargets2
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
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. Yuan CS: Methylnaltrexone mechanisms of action and effects on opioid bowel dysfunction and other opioid adverse effects. Ann Pharmacother. 2007 Jun;41(6):984-93. Epub 2007 May 15. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Antagonist
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
References
  1. Yuan CS: Methylnaltrexone mechanisms of action and effects on opioid bowel dysfunction and other opioid adverse effects. Ann Pharmacother. 2007 Jun;41(6):984-93. Epub 2007 May 15. [Article]

Drug created at September 14, 2010 16:21 / Updated at December 03, 2021 01:12