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Identification
Name Naltrexone
Accession Number DB00704 (APRD00005, DB05067)
Type small molecule
Groups approved
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
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
PTI-555
Salts Not Available
Brand names
Name Company
Celupan
MorViva
N-Cyclopropylmethylnoroxymorphone
Naltrexona [INN-Spanish]
Naltrexone [Usan:Ban:Inn]
Naltrexone Hcl
Naltrexonum [INN-Latin]
ReVia
Vivitrex
Brand mixtures Not Available
Categories
  • Anti-craving Agents
  • Narcotic Antagonists
  • Depressants
  • Alcohol Antagonists
  • Opiate Antagonists
CAS number 16590-41-3
Weight Average: 341.4009
Monoisotopic: 341.162708229
Chemical Formula C20H23NO4
InChI Key InChIKey=DQCKKXVULJGBQN-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
Plain Text
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
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Morphinans
  • Benzylisoquinolines
Substructures
  • Morphinans
  • Benzofurans
  • Hydroxy Compounds
  • Naphthalenes
  • Phenols and Derivatives
  • Benzylisoquinolines
  • Cyclopropane and Derivatives
  • Ethers
  • Benzene and Derivatives
  • Phenylpiperidines
  • Methoxyphenols
  • Aliphatic and Aryl Amines
  • Alcohols and Polyols
  • Phenanthrenes
  • Catechols
  • Phenethylamines
  • Heterocyclic compounds
  • Aromatic compounds
  • Anisoles
  • Phenylpropylamines
  • (Iso)quinolines and Derivatives
  • Cyclohexenes and Derivatives
  • Phenyl Esters
  • Amphetamines
  • Catecholamines and Derivatives
  • Piperidines
  • Ketones
Pharmacology
Indication Used 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.
Pharmacodynamics Naltrexone, 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 action Naltrexone 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.
Absorption Although 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 binding 21% 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.
Route of elimination Both 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 life 4 hours for naltrexone and 13 hours for the active metabolite 6 beta-naltrexol.
Clearance
  • ~ 3.5 L/min [after IV administration]
Toxicity In 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 Not Available
Pharmacoeconomics
Manufacturers
  • Alkermes inc
  • Actavis totowa llc
  • Barr laboratories inc
  • Mallinckrodt inc
  • Sandoz inc
  • Duramed pharmaceuticals inc
Packagers
Dosage forms
Form Route Strength
Tablet Oral
Prices
Unit description Cost Unit
Vivitrol injectable suspension 960.0 USD each
ReVia 30 50 mg tablet Bottle 291.73 USD bottle
Naltrexone hcl powder 172.54 USD g
Naltrexone powder 69.0 USD g
Revia 50 mg tablet 9.35 USD tablet
Naltrexone 50 mg tablet 4.57 USD tablet
Naltrexone HCl 50 mg tablet 4.45 USD tablet
Depade 50 mg tablet 4.28 USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Country Patent Number Approved Expires (estimated)
United States 6495164 2000-05-25 2020-05-25
United States 5792477 1997-05-02 2017-05-02
Properties
State solid
Experimental Properties
Property Value Source
melting point 168-170 °C PhysProp
water solubility 100 mg/mL (as hydrochloride salt) Not Available
logP 1.92 HANSCH,C ET AL. (1995)
Predicted Properties
Property Value Source
water solubility 3.07e+00 g/l ALOGPS
logP 2.07 ALOGPS
logP 1.36 ChemAxon
logS -2 ALOGPS
pKa (strongest acidic) 7.39 ChemAxon
pKa (strongest basic) 11.54 ChemAxon
physiological charge 1 ChemAxon
hydrogen acceptor count 5 ChemAxon
hydrogen donor count 2 ChemAxon
polar surface area 70 ChemAxon
rotatable bond count 2 ChemAxon
refractivity 91.5 ChemAxon
polarizability 35.97 ChemAxon
References
Synthesis Reference Not Available
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
Resource Link
KEGG Drug D05113 Link_out
KEGG Compound C07253 Link_out
PubChem Compound 5360515 Link_out
PubChem Substance 46505333 Link_out
ChemSpider 4514524 Link_out
ChEBI 7465 Link_out
ChEMBL 7465 Link_out
Therapeutic Targets Database DAP000379 Link_out
PharmGKB PA450588 Link_out
Drug Product Database 2213826 Link_out
RxList http://www.rxlist.com/cgi/generic2/naltrexone.htm Link_out
Drugs.com http://www.drugs.com/cdi/naltrexone.html Link_out
PDRhealth http://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/rev1376.shtml Link_out
Wikipedia http://en.wikipedia.org/wiki/Naltrexone Link_out
ATC Codes
  • N07BB04
AHFS Codes
  • 28:10.00
PDB Entries Not Available
FDA label show (1.83 MB)
MSDS show (73.9 KB)
Interactions
Drug Interactions Not Available
Food Interactions
  • Take without regard to meals.
Targets

1. Delta-type opioid receptor

Pharmacological action: yes
Actions: antagonist

Inhibits neurotransmitter release by reducing calcium ion currents and increasing potassium ion conductance. Highly stereoselective. receptor for enkephalins

Organism class: human
UniProt ID: P41143 Link_out
Gene: OPRD1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Pharmacological action: yes
Actions: antagonist

Inhibits neurotransmitter release by reducing calcium ion currents and increasing potassium ion conductance. Receptor for beta-endorphin

Organism class: human
UniProt ID: P35372 Link_out
Gene: OPRM1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Pharmacological action: yes
Actions: antagonist

Inhibits neurotransmitter release by reducing calcium ion currents and increasing potassium ion conductance. Receptor for dynorphins. May play a role in arousal and regulation of autonomic and neuroendocrine functions

Organism class: human
UniProt ID: P41145 Link_out
Gene: OPRK1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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. Opioid receptor, sigma 1

Pharmacological action: yes
Actions: antagonist
Organism class: human
UniProt ID: Q5T1J1 Link_out
Gene: OPRS1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate

UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX- alpha to form both the IX-alpha-C8 and IX-alpha-C12 monoconjugates and diconjugate

UniProt ID: P22309 Link_out
Gene: UGT1A1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: inhibitor

Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells

UniProt ID: P08183 Link_out
Gene: ABCB1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:19