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Identification
NameMethylnaltrexone
Accession NumberDB06800
TypeSmall Molecule
GroupsApproved
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 Identifiers
  • MRZ 2663BR
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Relistorinjection, solution12 mg/.6mLsubcutaneousSalix Pharmaceuticals, Inc.2008-08-01Not applicableUs
Relistorsolution20 mgsubcutaneousSalix Pharmaceuticals IncNot applicableNot applicableCanada
Relistorsolution20 mgsubcutaneousSalix Pharmaceuticals IncNot applicableNot applicableCanada
Relistorsolution20 mgsubcutaneousSalix Pharmaceuticals Inc2008-05-07Not applicableCanada
RelistorkitSalix Pharmaceuticals, Inc.2008-08-012016-03-01Us
Relistorinjection, solution8 mg/.4mLsubcutaneousSalix Pharmaceuticals, Inc.2012-02-01Not applicableUs
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Methylnaltrexone bromide
916055-92-0
Thumb
  • InChI Key: IFGIYSGOEZJNBE-NQMNLMSRSA-N
  • Monoisotopic Mass: 435.104521
  • Average Mass: 436.346
DBSALT000116
Categories
UNII0RK7M7IABE
CAS number916055-93-1
WeightAverage: 356.441
Monoisotopic: 356.185634741
Chemical FormulaC21H26NO4
InChI KeyJVLBPIPGETUEET-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[[email protected]]4OC5=C(O)C=CC(C[C@@H]1[C@]2(O)CCC4=O)=C35
Taxonomy
DescriptionThis 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.
KingdomOrganic compounds
Super ClassBenzenoids
ClassPhenanthrenes and derivatives
Sub ClassNot Available
Direct ParentPhenanthrenes and derivatives
Alternative Parents
Substituents
  • Phenanthrene
  • Isoquinolone
  • Tetralin
  • Coumaran
  • 1-hydroxy-2-unsubstituted benzenoid
  • Alkyl aryl ether
  • Aralkylamine
  • Phenol
  • Piperidine
  • Cyclic alcohol
  • Tetraalkylammonium salt
  • Tertiary alcohol
  • Quaternary ammonium salt
  • 1,2-aminoalcohol
  • Ketone
  • Ether
  • Oxacycle
  • Azacycle
  • Organoheterocyclic compound
  • Organonitrogen compound
  • Alcohol
  • Hydrocarbon derivative
  • Organic nitrogen compound
  • Organic oxide
  • Carbonyl group
  • Organooxygen compound
  • Organic oxygen compound
  • Amine
  • Organic cation
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationTreatment of opioids induced constipation in palliative patients that are inadequately responding to laxative therapy.
PharmacodynamicsUse 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 actionMethylnaltrexone 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.
Related Articles
AbsorptionMethylnaltrexone 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 binding11% 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 eliminationMost 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 lifeterminal: 8.89 ± 2.59 h (intravenous) terminal: 6.14- 8.83 h (subcutaneous)
Clearance

10.5 ± 1.5 ml/min/kg (IV)

ToxicityLD50: 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
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
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 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Injection, solutionsubcutaneous12 mg/.6mL
Injection, solutionsubcutaneous8 mg/.4mL
Kit
Solutionsubcutaneous20 mg
PricesNot Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US6559158 No1997-11-032017-11-03Us
US8247425 No2010-12-312030-12-31Us
US8420663 No2009-09-302029-09-30Us
US8552025 No2004-04-082024-04-08Us
US8822490 No2009-09-302029-09-30Us
US9180125 No2009-09-302029-09-30Us
Properties
StateSolid
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 FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot 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
ATC CodesA06AH01
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelDownload (4.17 MB)
MSDSDownload (479 KB)
Interactions
Drug Interactions
Drug
AlvimopanThe risk or severity of adverse effects can be increased when Methylnaltrexone is combined with Alvimopan.
NaloxegolThe risk or severity of adverse effects can be increased when Methylnaltrexone is combined with Naloxegol.
NaloxoneThe risk or severity of adverse effects can be increased when Methylnaltrexone is combined with Naloxone.
NaltrexoneThe risk or severity of adverse effects can be increased when MethylNaltrexone is combined with Naltrexone.
Food InteractionsNot 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. Agonist binding to the receptor induces coupling to an inactive GDP-bound heterotrimeric G-protein complex and subsequent exchange of GDP for GTP in the G-protein alpha subunit leading to dissociati...
Gene Name:
OPRM1
Uniprot ID:
P35372
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 synthetic opioids and for the psychoactive diterpene salvinorin A. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates th...
Gene Name:
OPRK1
Uniprot ID:
P41145
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 antidepressants.
Gene Name:
CYP2D6
Uniprot ID:
P10635
Molecular Weight:
55768.94 Da
Comments
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Drug created on September 14, 2010 10:21 / Updated on August 24, 2016 01:51