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Identification
NameNaltrexone
Accession NumberDB00704  (APRD00005, DB05067)
Typesmall molecule
Groupsapproved, investigational
Description

Derivative of noroxymorphone that is the N-cyclopropylmethyl congener of naloxone. It is a narcotic antagonist that is effective orally, longer lasting and more potent than naloxone, and has been proposed for the treatment of heroin addiction. The FDA has approved naltrexone for the treatment of alcohol dependence. [PubChem]

Structure
Thumb
Synonyms
SynonymLanguageCode
17-(Cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxymorphinan-6-oneNot AvailableNot Available
17-(Cyclopropylmethyl)-4,5alpha-epoxy-3,14-dihydroxymorphinan-6-oneNot AvailableNot Available
N-Cyclopropylmethyl-14-hydroxydihydromorphinoneNot AvailableNot Available
N-CyclopropylmethylnoroxymorphoneNot AvailableNot Available
NaltrexonGermanINN
NaltrexonaSpanishINN
NaltrexoneNot AvailableINN, BAN, USAN
NaltrexonumLatinINN
Salts
Name/CAS Structure Properties
Naltrexone Hydrochloride
Thumb
  • InChI Key: RHBRMCOKKKZVRY-ITLPAZOVSA-N
  • Monoisotopic Mass: 377.139385968
  • Average Mass: 377.862
DBSALT000670
Brand names
NameCompany
AbernilMedochemie
AdependAOP Orphan
AntaxonZambon
AntaxonePharmazam
ArropQuimico
CelupanNot Available
DepadeNot Available
DependexAmomed
MorVivaNot Available
NaleronaABL Pharma
NalorexBristol-Myers Squibb
NaltaxNavana
NaltreksonWyeth
NarcoralSirton
NeksiGMP
NemexinBristol-Myers Squibb
OpizoneBritannia
RevezSoubeiran Chobet
ReviaBristol Myers Squibb
TrexanDu Pont
VivitrexNot Available
VivitrolJohnson & Johnson
Brand mixtures
Brand NameIngredients
EmbedaNaltrexone and Morphine
Categories
CAS number16590-41-3
WeightAverage: 341.4009
Monoisotopic: 341.162708229
Chemical FormulaC20H23NO4
InChI KeyDQCKKXVULJGBQN-XFWGSAIBSA-N
InChI
InChI=1S/C20H23NO4/c22-13-4-3-12-9-15-20(24)6-5-14(23)18-19(20,16(12)17(13)25-18)7-8-21(15)10-11-1-2-11/h3-4,11,15,18,22,24H,1-2,5-10H2/t15-,18+,19+,20-/m1/s1
IUPAC Name
(1S,5R,13R,17S)-4-(cyclopropylmethyl)-10,17-dihydroxy-12-oxa-4-azapentacyclo[9.6.1.0^{1,13}.0^{5,17}.0^{7,18}]octadeca-7(18),8,10-trien-14-one
SMILES
[H][C@@]12OC3=C(O)C=CC4=C3[C@@]11CCN(CC3CC3)[C@]([H])(C4)[C@]1(O)CCC2=O
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassAlkaloids and Derivatives
ClassMorphinans
SubclassNot Available
Direct parentMorphinans
Alternative parentsBenzylisoquinolines; Phenanthrenes and Derivatives; Isoquinolones and Derivatives; Tetralins; Benzofurans; Phenols and Derivatives; Alkyl Aryl Ethers; Cyclohexanols; Cyclohexanones; Piperidines; Tertiary Alcohols; Cyclic Alcohols and Derivatives; Tertiary Amines; Polyamines; Enols
Substituentsphenanthrene; isoquinolone; tetralin; benzofuran; cyclohexanone; phenol derivative; cyclohexanol; alkyl aryl ether; piperidine; benzene; tertiary alcohol; cyclic alcohol; tertiary amine; ketone; ether; polyamine; enol; amine; carbonyl group; organonitrogen compound; alcohol
Classification descriptionThis compound belongs to the morphinans. These are polycyclic compounds with a four-ring skeleton with three condensed six-member rings forming a partially hydrogenated phenanthrene moiety, one of which is aromatic while the two others are alicyclic.
Pharmacology
IndicationUsed as an adjunct to a medically supervised behaviour modification program in the maintenance of opiate cessation in individuals who were formerly physically dependent on opiates and who have successfully undergone detoxification. Also used for the management of alcohol dependence in conjunction with a behavioural modification program.
PharmacodynamicsNaltrexone, a pure opioid antagonist, is a synthetic congener of oxymorphone with no opioid agonist properties. Naltrexone is indicated in the treatment of alcohol dependence and for the blockade of the effects of exogenously administered opioids. It markedly attenuates or completely blocks, reversibly, the subjective effects of intravenously administered opioids. When co-administered with morphine, on a chronic basis, naltrexone blocks the physical dependence to morphine, heroin and other opioids. In subjects physically dependent on opioids, naltrexone will precipitate withdrawal symptomatology.
Mechanism of actionNaltrexone is a pure opiate antagonist and has little or no agonist activity. The mechanism of action of naltrexone in alcoholism is not understood; however, involvement of the endogenous opioid system is suggested by preclinical data. Naltrexone is thought to act as a competitive antagonist at mc, κ, and δ receptors in the CNS, with the highest affintiy for the μ receptor. Naltrexone competitively binds to such receptors and may block the effects of endogenous opioids. This leads to the antagonization of most of the subjective and objective effects of opiates, including respiratory depression, miosis, euphoria, and drug craving. The major metabolite of naltrexone, 6-β-naltrexol, is also an opiate antagonist and may contribute to the antagonistic activity of the drug.
AbsorptionAlthough well absorbed orally, naltrexone is subject to significant first pass metabolism with oral bioavailability estimates ranging from 5 to 40%.
Volume of distribution
  • 1350 L [intravenous administration]
Protein binding21% bound to plasma proteins over the therapeutic dose range.
Metabolism

Hepatic. When administered orally, naltrexone undergoes extensive biotransformation and is metabolized to 6 beta-naltrexol (which may contribute to the therapeutic effect) and other minor metabolites.

SubstrateEnzymesProduct
Naltrexone
Not Available
6-beta-naltrexolDetails
Route of eliminationBoth parent drug and metabolites are excreted primarily by the kidney (53% to 79% of the dose), however, urinary excretion of unchanged naltrexone accounts for less than 2% of an oral dose and fecal excretion is a minor elimination pathway. The renal clearance for naltrexone ranges from 30 to 127 mL/min and suggests that renal elimination is primarily by glomerular filtration.
Half life4 hours for naltrexone and 13 hours for the active metabolite 6 beta-naltrexol.
Clearance
  • ~ 3.5 L/min [after IV administration]
ToxicityIn the mouse, rat and guinea pig, the oral LD50s were 1,100-1,550 mg/kg; 1,450 mg/kg; and 1,490 mg/kg; respectively. High doses of naltrexone (generally ≥1,000 mg/kg) produce salivation, depression/reduced activity, tremors, and convulsions.
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategorySMPDB ID
Naltrexone Action PathwayDrug actionSMP00687
SNP Mediated Effects
Interacting Gene/EnzymeSNP RS IDAllele nameDefining changeEffectReference(s)
Mu-type opioid receptor
Gene symbol: OPRM1
UniProt: P35372
rs1799971 Not AvailableA > GThose with the AG genotype respond better to therapy (increase number of abstinent days)18250251
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9769
Blood Brain Barrier + 0.9671
Caco-2 permeable + 0.7471
P-glycoprotein substrate Substrate 0.8685
P-glycoprotein inhibitor I Non-inhibitor 0.8867
P-glycoprotein inhibitor II Non-inhibitor 0.8718
Renal organic cation transporter Non-inhibitor 0.5189
CYP450 2C9 substrate Non-substrate 0.8336
CYP450 2D6 substrate Substrate 0.5925
CYP450 3A4 substrate Substrate 0.5981
CYP450 1A2 substrate Inhibitor 0.6656
CYP450 2C9 substrate Non-inhibitor 0.9355
CYP450 2D6 substrate Non-inhibitor 0.5686
CYP450 2C19 substrate Non-inhibitor 0.9354
CYP450 3A4 substrate Non-inhibitor 0.8993
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9483
Ames test Non AMES toxic 0.6324
Carcinogenicity Non-carcinogens 0.96
Biodegradation Not ready biodegradable 0.9939
Rat acute toxicity 2.7174 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.861
hERG inhibition (predictor II) Non-inhibitor 0.8446
Pharmacoeconomics
Manufacturers
  • Alkermes inc
  • Actavis totowa llc
  • Barr laboratories inc
  • Mallinckrodt inc
  • Sandoz inc
  • Duramed pharmaceuticals inc
Packagers
Dosage forms
FormRouteStrength
TabletOral
Prices
Unit descriptionCostUnit
Vivitrol injectable suspension960.0USDeach
ReVia 30 50 mg tablet Bottle291.73USDbottle
Naltrexone hcl powder172.54USDg
Naltrexone powder69.0USDg
Revia 50 mg tablet9.35USDtablet
Naltrexone 50 mg tablet4.57USDtablet
Naltrexone HCl 50 mg tablet4.45USDtablet
Depade 50 mg tablet4.28USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States64951642000-05-252020-05-25
United States57924771997-05-022017-05-02
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point168-170 °CPhysProp
water solubility100 mg/mL (as hydrochloride salt)Not Available
logP1.92HANSCH,C ET AL. (1995)
Predicted Properties
PropertyValueSource
water solubility3.07e+00 g/lALOGPS
logP2.07ALOGPS
logP1.36ChemAxon
logS-2ALOGPS
pKa (strongest acidic)7.39ChemAxon
pKa (strongest basic)11.54ChemAxon
physiological charge1ChemAxon
hydrogen acceptor count5ChemAxon
hydrogen donor count2ChemAxon
polar surface area70ChemAxon
rotatable bond count2ChemAxon
refractivity91.5ChemAxon
polarizability35.97ChemAxon
number of rings6ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Bao-Shan Huang, Yansong Lu, Ben-Yi Ji, Aris P Christodoulou, “Preparation of naltrexone from codeine and 3-benzylmorphine.” U.S. Patent US6013796, issued March, 1990.

US6013796
General Reference
  1. Schmitz JM, Stotts AL, Rhoades HM, Grabowski J: Naltrexone and relapse prevention treatment for cocaine-dependent patients. Addict Behav. 2001 Mar-Apr;26(2):167-80. Pubmed
  2. Krystal JH, Gueorguieva R, Cramer J, Collins J, Rosenheck R: Naltrexone is associated with reduced drinking by alcohol dependent patients receiving antidepressants for mood and anxiety symptoms: results from VA Cooperative Study No. 425, “Naltrexone in the treatment of alcoholism”. Alcohol Clin Exp Res. 2008 Jan;32(1):85-91. Epub 2007 Dec 7. Pubmed
  3. Ray LA, Chin PF, Miotto K: Naltrexone for the treatment of alcoholism: clinical findings, mechanisms of action, and pharmacogenetics. CNS Neurol Disord Drug Targets. 2010 Mar;9(1):13-22. Pubmed
External Links
ResourceLink
KEGG DrugD05113
KEGG CompoundC07253
PubChem Compound5360515
PubChem Substance46505333
ChemSpider4514524
ChEBI7465
ChEMBLCHEMBL19019
Therapeutic Targets DatabaseDAP000379
PharmGKBPA450588
Drug Product Database2213826
RxListhttp://www.rxlist.com/cgi/generic2/naltrexone.htm
Drugs.comhttp://www.drugs.com/cdi/naltrexone.html
PDRhealthhttp://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/rev1376.shtml
WikipediaNaltrexone
ATC CodesN07BB04
AHFS Codes
  • 28:10.00
PDB EntriesNot Available
FDA labelshow(1.83 MB)
MSDSshow(73.9 KB)
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

Targets

1. Delta-type opioid receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
Delta-type opioid receptor P41143 Details

References:

  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. Roy S, Guo X, Kelschenbach J, Liu Y, Loh HH: In vivo activation of a mutant mu-opioid receptor by naltrexone produces a potent analgesic effect but no tolerance: role of mu-receptor activation and delta-receptor blockade in morphine tolerance. J Neurosci. 2005 Mar 23;25(12):3229-33. Pubmed
  3. Barrios de Tomasi E, Juarez-Gonzalez J: [Opioid antagonists and alcohol consumption] Rev Neurol. 2007 Aug 1-15;45(3):155-62. Pubmed
  4. Weerts EM, Kim YK, Wand GS, Dannals RF, Lee JS, Frost JJ, McCaul ME: Differences in delta- and mu-opioid receptor blockade measured by positron emission tomography in naltrexone-treated recently abstinent alcohol-dependent subjects. Neuropsychopharmacology. 2008 Feb;33(3):653-65. Epub 2007 May 9. Pubmed
  5. Herz A: Opioid reward mechanisms: a key role in drug abuse? Can J Physiol Pharmacol. 1998 Mar;76(3):252-8. Pubmed
  6. Herz A: Endogenous opioid systems and alcohol addiction. Psychopharmacology (Berl). 1997 Jan;129(2):99-111. Pubmed

2. Mu-type opioid receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
Mu-type opioid receptor P35372 Details

References:

  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. Kato H: [Pharmacological effects of a mu-opioid receptor antagonist naltrexone on alcohol dependence] Nihon Arukoru Yakubutsu Igakkai Zasshi. 2008 Oct;43(5):697-704. Pubmed
  3. Helm S, Trescot AM, Colson J, Sehgal N, Silverman S: Opioid antagonists, partial agonists, and agonists/antagonists: the role of office-based detoxification. Pain Physician. 2008 Mar-Apr;11(2):225-35. Pubmed
  4. Goodman AJ, Le Bourdonnec B, Dolle RE: Mu opioid receptor antagonists: recent developments. ChemMedChem. 2007 Nov;2(11):1552-70. Pubmed
  5. Barrios de Tomasi E, Juarez-Gonzalez J: [Opioid antagonists and alcohol consumption] Rev Neurol. 2007 Aug 1-15;45(3):155-62. Pubmed
  6. Weerts EM, Kim YK, Wand GS, Dannals RF, Lee JS, Frost JJ, McCaul ME: Differences in delta- and mu-opioid receptor blockade measured by positron emission tomography in naltrexone-treated recently abstinent alcohol-dependent subjects. Neuropsychopharmacology. 2008 Feb;33(3):653-65. Epub 2007 May 9. Pubmed
  7. Herz A: Opioid reward mechanisms: a key role in drug abuse? Can J Physiol Pharmacol. 1998 Mar;76(3):252-8. Pubmed

3. Kappa-type opioid receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
Kappa-type opioid receptor P41145 Details

References:

  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. Helm S, Trescot AM, Colson J, Sehgal N, Silverman S: Opioid antagonists, partial agonists, and agonists/antagonists: the role of office-based detoxification. Pain Physician. 2008 Mar-Apr;11(2):225-35. Pubmed
  3. Herz A: Endogenous opioid systems and alcohol addiction. Psychopharmacology (Berl). 1997 Jan;129(2):99-111. Pubmed
  4. Barrios de Tomasi E, Juarez-Gonzalez J: [Opioid antagonists and alcohol consumption] Rev Neurol. 2007 Aug 1-15;45(3):155-62. Pubmed
  5. Wee S, Orio L, Ghirmai S, Cashman JR, Koob GF: Inhibition of kappa opioid receptors attenuated increased cocaine intake in rats with extended access to cocaine. Psychopharmacology (Berl). 2009 Sep;205(4):565-75. Epub 2009 May 30. Pubmed

4. HCG20471, isoform CRA_c

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
HCG20471, isoform CRA_c Q5T1J1 Details

References:

  1. Helm S, Trescot AM, Colson J, Sehgal N, Silverman S: Opioid antagonists, partial agonists, and agonists/antagonists: the role of office-based detoxification. Pain Physician. 2008 Mar-Apr;11(2):225-35. Pubmed
  2. Wee S, Orio L, Ghirmai S, Cashman JR, Koob GF: Inhibition of kappa opioid receptors attenuated increased cocaine intake in rats with extended access to cocaine. Psychopharmacology (Berl). 2009 Sep;205(4):565-75. Epub 2009 May 30. Pubmed
  3. Herz A: Endogenous opioid systems and alcohol addiction. Psychopharmacology (Berl). 1997 Jan;129(2):99-111. Pubmed

Enzymes

1. UDP-glucuronosyltransferase 1-1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
UDP-glucuronosyltransferase 1-1 P22309 Details

References:

  1. Antonilli L, Brusadin V, Milella MS, Sobrero F, Badiani A, Nencini P: In vivo chronic exposure to heroin or naltrexone selectively inhibits liver microsome formation of estradiol-3-glucuronide in the rat. Biochem Pharmacol. 2008 Sep 1;76(5):672-9. Epub 2008 Jul 1. Pubmed

Transporters

1. Multidrug resistance protein 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Multidrug resistance protein 1 P08183 Details

References:

  1. Mahar Doan KM, Humphreys JE, Webster LO, Wring SA, Shampine LJ, Serabjit-Singh CJ, Adkison KK, Polli JW: Passive permeability and P-glycoprotein-mediated efflux differentiate central nervous system (CNS) and non-CNS marketed drugs. J Pharmacol Exp Ther. 2002 Dec;303(3):1029-37. Pubmed

Comments
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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:11