Identification

Name
Nalmefene
Accession Number
DB06230
Type
Small Molecule
Groups
Approved, Investigational, Withdrawn
Description

Nalmefene is a 6-methylene analogue of naltrexone and opioid system modulator but with no opioid activity [Label]. It mediates a partial agonist effect on kappa receptors [2]. It is primarily used in the management of alcohol dependence in adult patients in conjunction with continuous psychosocial support focused on treatment adherence and reducing alcohol consumption [4] when it is exists as the hydrochloride dihydrate form under the trade name Selincro. Selincro is orally administered as tablets. Nalmefene works to reduce alcohol consumption in individuals by positive reward effect of alcohol which involves the opioid system, as well as the sedative and dysphoric properties of alcohol [2].

It is also indicated to prevent or reverse the effects of opioids, including respiratory depression, sedation, and hypotension by acting on the opioid receptor as an antagonist [Label] under the trade name Revex for intramuscular, intravenous and subcutaneous injection, where nalmefene hydrochloride is an active ingredient.

Structure
Thumb
Synonyms
Not Available
External IDs
JF-1 / ORF 1167 / ORF 11676 / ORF-1167 / ORF-11676 / SRD-174 / SRD174
Product Ingredients
IngredientUNIICASInChI Key
Nalmefene hydrochlorideK7K69QC05X58895-64-0GYWMRGWFQPSQLK-OPHZJPRHSA-N
Nalmefene hydrochloride dihydrate52Z0G7QVJX1228646-70-5XOBQQQVDLSMXCE-JVRGSUDVSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
SelincroTablet, film coated18 mgOralH. Lundbeck A/S2013-02-25Not applicableEu
SelincroTablet, film coated18 mgOralH. Lundbeck A/S2013-02-25Not applicableEu
SelincroTablet, film coated18 mgOralH. Lundbeck A/S2013-02-25Not applicableEu
SelincroTablet, film coated18 mgOralH. Lundbeck A/S2013-02-25Not applicableEu
SelincroTablet, film coated18 mgOralH. Lundbeck A/S2013-02-25Not applicableEu
SelincroTablet, film coated18 mgOralH. Lundbeck A/S2013-02-25Not applicableEu
SelincroTablet, film coated18 mgOralH. Lundbeck A/S2013-02-25Not applicableEu
SelincroTablet, film coated18 mgOralH. Lundbeck A/S2013-02-25Not applicableEu
Unapproved/Other Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
RevexNalmefene hydrochloride (0.1 mg/1mL)Injection, solutionIntravenousBaxter Laboratories2006-06-19Not applicableUs
RevexNalmefene hydrochloride (1 mg/1mL)Injection, solutionIntravenousBaxter Laboratories2006-06-19Not applicableUs
International/Other Brands
Revex (Somaxon Pharmaceuticals, Inc.) / Selincro (Lundbeck)
Categories
UNII
TOV02TDP9I
CAS number
55096-26-9
Weight
Average: 339.435
Monoisotopic: 339.183443669
Chemical Formula
C21H25NO3
InChI Key
WJBLNOPPDWQMCH-MBPVOVBZSA-N
InChI
InChI=1S/C21H25NO3/c1-12-6-7-21(24)16-10-14-4-5-15(23)18-17(14)20(21,19(12)25-18)8-9-22(16)11-13-2-3-13/h4-5,13,16,19,23-24H,1-3,6-11H2/t16-,19+,20+,21-/m1/s1
IUPAC Name
(1S,5R,13S,17S)-4-(cyclopropylmethyl)-14-methylidene-12-oxa-4-azapentacyclo[9.6.1.0^{1,13}.0^{5,17}.0^{7,18}]octadeca-7(18),8,10-triene-10,17-diol
SMILES
[H][C@@]12OC3=C(O)C=CC4=C3[C@@]11CCN(CC3CC3)[C@]([H])(C4)[C@]1(O)CCC2=C

Pharmacology

Indication

Indicated for the reduction of alcohol consumption in adult patients with alcohol dependence who have a high drinking risk level (DRL), without physical withdrawal symptoms and who do not require immediate detoxification [4].

Indicated for the complete or partial reversal of opioid drug effects, including respiratory depression - induced by either natural or synthetic opioids - or in the management of known or suspected opioid overdose [Label].

Associated Conditions
Pharmacodynamics

Nalmefene has not been shown to produce tolerance, physical dependence, or abuse potential [4].

When adminsitered as an antidote for opioid overdose, nalmefene is not known to produce any respiratory depression, psychomimetic effects, or pupillary constriction [Label]. In the absence of opioid agonists, there was no observable pharmacological activity. Nalmefene injection can produce acute withdrawal symptoms in individuals who are opioid-dependent.

Mechanism of action

Nalmefene is an opioid system modulator with a distinct μ, δ, and κ receptor profile. It acts as a selective opioid receptor ligand with antagonist activity at the μ and δ receptors and partial agonist activity at the κ receptor [4, 2]. Animal studies suggest that the kappa receptor signalling responses lead to antagonism of acute reward and positive reinforcement effects of drugs by decreasing dopamine in the nucleus accumbens [2]. Thus it is suggested that nalmefene may be more effective treatment for alcohol dependence than Naltrexone, which is a pure mu and delta receptor antagonist [2]. In vivo studies and rat studies have demonstrated that nalmefene reduces self-administration of alcohol, possibly by modulating cortico-mesolimbic functions [4].

Nalmefene, a 6-methylene analogue of naltrexone, is a competitive opioid antagonist which binds with high affinity to the mu opioid receptor. Nalmefene itself does not induce any opioid activity, but prevents or reverses the effects of opioids such as respiratory depression and sedation when injected[Label]. Some pharmacodynamic studies showed that nalmefene has a longer duration of action than naloxone at fully reversing doses [Label] however the relative potency of these two antagonists are reported to be similar [3].

TargetActionsOrganism
AMu-type opioid receptor
antagonist
Human
AKappa-type opioid receptor
partial agonist
Human
ADelta-type opioid receptor
antagonist
Human
Absorption

Following a single oral administration of 18.06 mg, nalmefene is rapidly absorbed with a peak plasma concentration (Cmax) of 16.5 ng/ml with the time to reach the peak concentration (Tmax) of approxmately 1.5 hours and the exposure (AUC) of 131 ng x h/ml. Although there is little association to clinical relevance, the AUC and Cmax values are expected to increase by 30 to 50%, respectively, and the Tmax is delayed by 30 minutes after consumption of high-fat food. The absolute oral bioavailability of nalmefene is 41% [4].

Nalmefene exhibits dose-proportional pharmacokinetics following intravenous injection. The Tmax following intramuscular or subcutaneous injection is approximately 1.5-2.3 hours. In an emergency setting, however, therapeutic plasma concentrations are likely to be reached within 5-15 minutes after a 1 mg dose given intravenously where the plasma concentration is approximately 3.7 ng/mL at 5 minutes in young adult males [Label].

Volume of distribution

The volume of distribution (Vd/F) of oral nalmefene is estimated to be approximately 3200 L [4]. According to a PET study after single and repeated daily dosing with 18.06 mg nalmefene, the drug displayed 94% to 100% receptor occupancy within 3 hours after dosing, indicating that nalmefene readily crosses the blood-brain barrier [4].

Nalmefene is reported to be rapidly distributed following a 1mg parenteral dose. Parenteral nalmefene also crosses the blood-brain barrier effectively, where the study of brain receptor occupancy demonstrated the blockage of over 80% of brain opioid receptors within 5 minutes after administration. The apparent volumes of distribution centrally (Vc) and at steady-state (Vdss) are 3.9 ± 1.1 L/kg and 8.6 ± 1.7 L/kg, respectively. In vitro study suggest that 67% of the drug is distributed into red blood cells and 39% of the drug distributed into plasma [Label].

Protein binding

The average protein-bound fraction of nalmefene in plasma is approximately 30-45% [4].

Metabolism

Following oral administration, nalmefene undergoes extensive hepatic metabolism where it is metabolized to the major inactive metabolite nalmefene 3-O-glucuronide via glucuronide conjugation. The major enzyme contributing to this reaction is UGT2B7, while UGT1A3 and UGT1A8 also play a minor role. A small proportion of nalmefene is also converted to nalmefene 3-O-sulfate by sulfation, which has a potency comparable to that of nalmefene. However nalmafene 3-O-sulfate is present in concentration less than 10% of that of nalmefene and is less likely to be a major contributor to the pharmacological action of the parent drug. Nalmefene may also be converted to nornalmefene via dealkylation by CYP3A4 or CYP3A5, which is further converted to nornalmefene 3-O-glucuronide and nornalmefene 3-O-sulfate with minimal pharmacological actions [4].

Route of elimination

Renal excretion is the main route of elimination for nalmefene and its metabolites. 54% of the total dose is excreted in the urine as nalmefene 3-O-glucuronide. Less than 3% of the dose is excreted as nalmefene or other metabolites [4]. Approximatly 17% of the total dose is reported to be excreted in the feces [Label].

Half life

The terminal half-life is approximately 12.5 hours following oral administration [4]. After intravenous administration of 1 mg in adult males, the terminal half life was 10.8 ± 5.2 hours [Label].

Clearance

The oral clearance of nalmefene (CL/F) was estimated as 169 L/h [4]. After intravenous administration of 1 mg in adult males, the systemic clearance of was 0.8 ± 0.2 L/hr/kg and the renal clearance was 0.08 ± 0.04 L/hr/kg [Label].

Toxicity

Studies in animals do not indicate direct effect in the reproductive system. In a rabbit embryo-foetal developmental toxicity study, reduced fetal weight and delayed ossification were observed in the fetus but did not result in abnormalities. Studies in rats have shown excretion of nalmefene or its metabolites in milk. The nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity, genotoxicity, or carcinogenic potential [4].

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

Interactions

Drug Interactions
DrugInteraction
AcetaminophenAcetaminophen may decrease the excretion rate of Nalmefene which could result in a higher serum level.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Nalmefene which could result in a higher serum level.
AlprazolamAlprazolam may decrease the excretion rate of Nalmefene which could result in a higher serum level.
AmilorideAmiloride may increase the excretion rate of Nalmefene which could result in a lower serum level and potentially a reduction in efficacy.
AmitriptylineNalmefene may decrease the excretion rate of Amitriptyline which could result in a higher serum level.
AmlodipineAmlodipine may decrease the excretion rate of Nalmefene which could result in a higher serum level.
AmoxicillinAmoxicillin may decrease the excretion rate of Nalmefene which could result in a higher serum level.
AmphetamineAmphetamine may decrease the excretion rate of Nalmefene which could result in a higher serum level.
AmpicillinAmpicillin may decrease the excretion rate of Nalmefene which could result in a higher serum level.
AuranofinAuranofin may decrease the excretion rate of Nalmefene which could result in a higher serum level.
Food Interactions
Not Available

References

General References
  1. Ingman K, Hagelberg N, Aalto S, Nagren K, Juhakoski A, Karhuvaara S, Kallio A, Oikonen V, Hietala J, Scheinin H: Prolonged central mu-opioid receptor occupancy after single and repeated nalmefene dosing. Neuropsychopharmacology. 2005 Dec;30(12):2245-53. [PubMed:15956985]
  2. Paille F, Martini H: Nalmefene: a new approach to the treatment of alcohol dependence. Subst Abuse Rehabil. 2014 Aug 8;5:87-94. doi: 10.2147/SAR.S45666. eCollection 2014. [PubMed:25187751]
  3. Glass PS, Jhaveri RM, Smith LR: Comparison of potency and duration of action of nalmefene and naloxone. Anesth Analg. 1994 Mar;78(3):536-41. [PubMed:8109774]
  4. European Medicines Agency (EMA) Summary of product characteristics: Selincro [Link]
External Links
KEGG Drug
D05111
KEGG Compound
C08027
ChemSpider
4447642
BindingDB
50045776
ChEBI
7457
ChEMBL
CHEMBL982
Wikipedia
Nalmefene
ATC Codes
N07BB05 — Nalmefene
FDA label
Download (69.6 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0TerminatedBasic ScienceAlcoholism1
1CompletedNot AvailableImpaired Renal Function1
1CompletedTreatmentAlcohol Dependence2
1CompletedTreatmentOpioid-Related Disorders1
1RecruitingOtherAlcohol Drinking1
1, 2RecruitingTreatmentAlcohol Use / Human Immunodeficiency Virus (HIV) Infections / Pain1
2CompletedTreatmentCessation, Smoking1
2CompletedTreatmentPruritus, Atopic Dermatitis1
2Not Yet RecruitingTreatmentImpulse Control Disorders / Parkinson's Disease (PD)1
2RecruitingTreatmentAlcohol Use Disorder (AUD)1
2RecruitingTreatmentHarmful; Use, Alcohol / Opioid-use Disorder1
2, 3CompletedTreatmentPathological Gambling1
3CompletedTreatmentAlcohol Dependence5
3Not Yet RecruitingTreatmentAlcohol Dependence / Liver Cirrhosis / Nalmefene1
4CompletedTreatmentAlcohol Dependence1
4TerminatedTreatmentAlcohol Dependence1
Not AvailableCompletedNot AvailableAlcohol Dependence1
Not AvailableRecruitingTreatmentAlcohol Use Disorder (AUD) / Borderline Personality Disorder (BPD)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, solutionIntravenous0.1 mg/1mL
Injection, solutionIntravenous1 mg/1mL
Tablet, film coatedOral18 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilityFreely soluble in water up to 130 mg/mLFDA Label
pKa7.6FDA Label
Predicted Properties
PropertyValueSource
Water Solubility0.839 mg/mLALOGPS
logP2.24ALOGPS
logP1.95ChemAxon
logS-2.6ALOGPS
pKa (Strongest Acidic)10.35ChemAxon
pKa (Strongest Basic)9.57ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area52.93 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity95.21 m3·mol-1ChemAxon
Polarizability37.27 Å3ChemAxon
Number of Rings6ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
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 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
Tetralins / Coumarans / Aralkylamines / Alkyl aryl ethers / 1-hydroxy-2-unsubstituted benzenoids / Piperidines / Tertiary alcohols / Trialkylamines / Cyclic alcohols and derivatives / 1,2-aminoalcohols
show 4 more
Substituents
Phenanthrene / Tetralin / Coumaran / 1-hydroxy-2-unsubstituted benzenoid / Alkyl aryl ether / Aralkylamine / Piperidine / Cyclic alcohol / Tertiary alcohol / 1,2-aminoalcohol
show 15 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
morphinane alkaloid (CHEBI:7457)

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
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Partial 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
References
  1. Kreek MJ, Schluger J, Borg L, Gunduz M, Ho A: Dynorphin A1-13 causes elevation of serum levels of prolactin through an opioid receptor mechanism in humans: gender differences and implications for modulation of dopaminergic tone in the treatment of addictions. J Pharmacol Exp Ther. 1999 Jan;288(1):260-9. [PubMed:9862779]
Kind
Protein
Organism
Human
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. Ingman K, Hagelberg N, Aalto S, Nagren K, Juhakoski A, Karhuvaara S, Kallio A, Oikonen V, Hietala J, Scheinin H: Prolonged central mu-opioid receptor occupancy after single and repeated nalmefene dosing. Neuropsychopharmacology. 2005 Dec;30(12):2245-53. [PubMed:15956985]
  2. Paille F, Martini H: Nalmefene: a new approach to the treatment of alcohol dependence. Subst Abuse Rehabil. 2014 Aug 8;5:87-94. doi: 10.2147/SAR.S45666. eCollection 2014. [PubMed:25187751]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Glucuronosyltransferase activity
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds.Its unique specificity for 3,4-catechol estrogens and estriol su...
Gene Name
UGT2B7
Uniprot ID
P16662
Uniprot Name
UDP-glucuronosyltransferase 2B7
Molecular Weight
60694.12 Da
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Retinoic acid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. Isoform 2 lacks transferase activity but acts as a negative reg...
Gene Name
UGT1A3
Uniprot ID
P35503
Uniprot Name
UDP-glucuronosyltransferase 1-3
Molecular Weight
60337.835 Da
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Steroid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. Isoform 2 lacks transferase activity but acts as a negative reg...
Gene Name
UGT1A8
Uniprot ID
Q9HAW9
Uniprot Name
UDP-glucuronosyltransferase 1-8
Molecular Weight
59741.035 Da

Drug created on March 19, 2008 10:18 / Updated on September 18, 2018 21:20