Methylnaltrexone

Identification

Name
Methylnaltrexone
Accession Number
DB06800
Type
Small Molecule
Groups
Approved
Description

Methylnaltrexone is a pheriphally-acting μ-opioid antagonists 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.

Structure
Thumb
Synonyms
  • MNTX
External IDs
MRZ 2663BR / MRZ-2663
Product Ingredients
IngredientUNIICASInChI Key
Methylnaltrexone bromideRFO6IL3D3M 916055-92-0IFGIYSGOEZJNBE-NQMNLMSRSA-N
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
RelistorInjection, solution12 mgSubcutaneousPharma Swiss Ceska Republika S.R.O2008-07-02Not applicableEu
RelistorInjection, solution12 mg/.6mLSubcutaneousSalix Pharmaceuticals2008-04-24Not applicableUs
RelistorKitSalix Pharmaceuticals2008-08-012016-03-01Us
RelistorSolution20 mgSubcutaneousSalix PharmaceuticalsNot applicableNot applicableCanada
RelistorInjection, solution12 mgSubcutaneousPharma Swiss Ceska Republika S.R.O2008-07-02Not applicableEu
RelistorInjection, solution8 mgSubcutaneousPharma Swiss Ceska Republika S.R.O2008-07-02Not applicableEu
RelistorSolution20 mgSubcutaneousSalix Pharmaceuticals2008-05-07Not applicableCanada
RelistorInjection, solution12 mgSubcutaneousPharma Swiss Ceska Republika S.R.O2008-07-02Not applicableEu
RelistorInjection, solution8 mg/.4mLSubcutaneousSalix Pharmaceuticals2008-04-24Not applicableUs
RelistorInjection, solution8 mgSubcutaneousPharma Swiss Ceska Republika S.R.O2008-07-02Not applicableEu
RelistorInjection, solution8 mgSubcutaneousPharma Swiss Ceska Republika S.R.O2008-07-02Not applicableEu
RelistorSolution20 mgSubcutaneousSalix PharmaceuticalsNot applicableNot applicableCanada
RelistorInjection, solution12 mgSubcutaneousPharma Swiss Ceska Republika S.R.O2008-07-02Not applicableEu
RelistorTablet150 mg/1OralSalix Pharmaceuticals2008-08-01Not applicableUs
RelistorInjection, solution8 mgSubcutaneousPharma Swiss Ceska Republika S.R.O2008-07-02Not applicableEu
Approved Generic Prescription Products
Not Available
Approved Over the Counter Products
Not Available
Unapproved/Other Products
Not Available
International/Other Brands
Not Available
Brand mixtures
Not Available
Categories
UNII
0RK7M7IABE
CAS number
916055-93-1
Weight
Average: 356.441
Monoisotopic: 356.185634741
Chemical Formula
C21H26NO4
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

Pharmacology

Indication

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

Structured Indications
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
Human
NKappa-type opioid receptor
antagonist
Human
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)

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.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteractionDrug group
AlvimopanThe risk or severity of adverse effects can be increased when Methylnaltrexone is combined with Alvimopan.Approved
BuprenorphineThe risk or severity of adverse effects can be increased when Methylnaltrexone is combined with Buprenorphine.Approved, Illicit, Investigational, Vet Approved
ButorphanolThe risk or severity of adverse effects can be increased when Methylnaltrexone is combined with Butorphanol.Approved, Illicit, Vet Approved
DextropropoxypheneThe risk or severity of adverse effects can be increased when Methylnaltrexone is combined with Dextropropoxyphene.Approved, Illicit, Withdrawn
DezocineThe risk or severity of adverse effects can be increased when Methylnaltrexone is combined with Dezocine.Approved
DiprenorphineThe risk or severity of adverse effects can be increased when Methylnaltrexone is combined with Diprenorphine.Illicit, Vet Approved
EluxadolineThe risk or severity of adverse effects can be increased when Methylnaltrexone is combined with Eluxadoline.Approved
FesoterodineThe serum concentration of the active metabolites of Fesoterodine can be increased when Fesoterodine is used in combination with Methylnaltrexone.Approved
LevallorphanThe risk or severity of adverse effects can be increased when Methylnaltrexone is combined with Levallorphan.Approved
LofexidineThe risk or severity of adverse effects can be increased when Methylnaltrexone is combined with Lofexidine.Approved, Investigational
MetoprololThe serum concentration of Metoprolol can be increased when it is combined with Methylnaltrexone.Approved, Investigational
NalbuphineThe risk or severity of adverse effects can be increased when Methylnaltrexone is combined with Nalbuphine.Approved
nalmefeneThe risk or severity of adverse effects can be increased when Methylnaltrexone is combined with nalmefene.Investigational
NalorphineThe risk or severity of adverse effects can be increased when Methylnaltrexone is combined with Nalorphine.Approved, Vet Approved
NaloxegolThe risk or severity of adverse effects can be increased when Methylnaltrexone is combined with Naloxegol.Approved
NaloxoneThe risk or severity of adverse effects can be increased when Methylnaltrexone is combined with Naloxone.Approved, Vet Approved
NaltrexoneThe risk or severity of adverse effects can be increased when Methylnaltrexone is combined with Naltrexone.Approved, Investigational, Vet Approved
OxymorphoneThe risk or severity of adverse effects can be increased when Methylnaltrexone is combined with Oxymorphone.Approved, Investigational, Vet Approved
PentazocineThe risk or severity of adverse effects can be increased when Methylnaltrexone is combined with Pentazocine.Approved, Vet Approved
ThioridazineThe serum concentration of Thioridazine can be increased when it is combined with Methylnaltrexone.Withdrawn
Food Interactions
Not Available

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. [PubMed:17981003 ]
  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. [PubMed:21222554 ]
  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. [PubMed:20053817 ]
  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. [PubMed:21836816 ]
External Links
KEGG Drug
D06618
ChemSpider
17248532
ChEMBL
CHEMBL1186579
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Methylnaltrexone
ATC Codes
A06AH01 — Methylnaltrexone bromide
AHFS Codes
Not Available
PDB Entries
Not Available
FDA label
Download (4.17 MB)
MSDS
Download (479 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedBasic ScienceIntestinal Obstruction2
1CompletedTreatmentHealthy Adult Subjects2
1CompletedTreatmentHealthy Adults2
1CompletedTreatmentHealthy Male Volunteers1
1CompletedTreatmentHealthy Males1
1CompletedTreatmentHealthy Volunteers2
1CompletedTreatmentImpaired Renal Function1
1CompletedTreatmentLiver Dysfunction1
1CompletedTreatmentNormal Healthy Volunteers1
1CompletedTreatmentNormal Volunteers1
1CompletedTreatmentOpioid Use, Unspecified With Other Opioid-induced Disorder1
2CompletedSupportive CareNeoplasms / Occasional Constipation / Opioid-Related Disorders1
2CompletedTreatmentBowel Dysfunction1
2CompletedTreatmentHealthy Volunteers1
2CompletedTreatmentOccasional Constipation1
2CompletedTreatmentOpioid Induced Constipation (OIC)1
2CompletedTreatmentPostoperative paralytic ileus1
2TerminatedTreatmentGastroparesis1
2, 3RecruitingTreatmentOpioid Induced Constipation (OIC)1
3CompletedTreatmentAdvance Illness Patients With OIC1
3CompletedTreatmentAdvanced Illness Patients With Opioid Induced Constipation1
3CompletedTreatmentOccasional Constipation2
3CompletedTreatmentOpioid Induced Constipation (OIC)1
3CompletedTreatmentPost Operative Bowel Dysfunction1
3CompletedTreatmentPost-Operative Ileus (POI)1
3CompletedTreatmentTerminal Illness2
3Unknown StatusTreatmentOpioid Induced Constipation (OIC)1
3WithdrawnTreatmentTube Feeding1
4CompletedTreatmentCoronary Artery Disease1
4CompletedTreatmentEsophageal Dysfunction / Pharyngeal Dysfunction1
4CompletedTreatmentGastric Motility Disorder1
4CompletedTreatmentOccasional Constipation1
4CompletedTreatmentOpioid Induced Constipation (OIC)1
4Not Yet RecruitingBasic SciencePharyngeal Dysfunction / Pharyngeal Swallowing1
4RecruitingPreventionOccasional Constipation1
4RecruitingTreatmentMethylnaltrexone / Morphine / ST Elevation Myocardial Infarction (STEMI) / Ticagrelor1
4Unknown StatusTreatmentOpioid Induced Constipation (OIC)1
4WithdrawnTreatmentColonic Inertia1
4WithdrawnTreatmentOpioid Induced Constipation (OIC)1
Not AvailableCompletedBasic ScienceEndogenous and Esophageal Sensitivity1
Not AvailableCompletedTreatmentOpioid Induced Constipation (OIC)1
Not AvailableTerminatedNot AvailableOccasional Constipation1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, solutionSubcutaneous12 mg
Injection, solutionSubcutaneous12 mg/.6mL
Injection, solutionSubcutaneous8 mg/.4mL
Injection, solutionSubcutaneous8 mg
Kit
SolutionSubcutaneous20 mg
TabletOral150 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8247425 No2010-12-312030-12-31Us
US8420663 No2009-09-302029-09-30Us
US8822490 No2009-09-302029-09-30Us
US9180125 No2009-09-302029-09-30Us
US8552025 No2004-04-082024-04-08Us
US6559158 No1997-11-032017-11-03Us
US9669096 No2004-04-082024-04-08Us
US9314461 No2011-03-102031-03-10Us
US8956651 No2011-03-102031-03-10Us
US8524276 No2011-03-102031-03-10Us
US9724343 No2009-09-302029-09-30Us

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

Taxonomy

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 7 more
Substituents
Phenanthrene / Isoquinolone / Tetralin / Coumaran / 1-hydroxy-2-unsubstituted benzenoid / Alkyl aryl ether / Aralkylamine / Phenol / Piperidine / Cyclic alcohol
show 20 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
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. [PubMed:17504835 ]
Kind
Protein
Organism
Human
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. [PubMed:17504835 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
Drug created on September 14, 2010 10:21 / Updated on September 01, 2017 11:31