Drug/Small Molecule:

naltrexone

Overview

Generic Names:	PTI-555; naltrexone
Trade Names:	Celupan; MorViva; N-Cyclopropylmethylnoroxymorphone; Naltrexona [INN-Spanish]; Naltrexone Hcl; Naltrexone [Usan:Ban:Inn]; Naltrexonum [INN-Latin]; ReVia; Vivitrex
PharmGKB Accession Id:	PA450588

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]

Indication

For use in the treatment of alcohol dependence and for the blockade of the effects of exogenously administered opioids.

ATC Therapeutic Category

• N07BB:Drugs used in alcohol dependence

Pharmacology and Interactions

Mechanism Of Action

Naltrexone binds to the opioid mu receptor antagonistically, thereby preventing conventional opiate (heroin, morphine) drugs from binding and inducing opioid neural responses. The mechanism of action of naltrexone in alcoholism is not understood; however, involvement of the endogenous opioid system is suggested by preclinical data. Naltrexone competitively binds to such receptors and may block the effects of endogenous opioids.

Pharmacology

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.

Food Interactions

Take without regard to meals.

Absorption, Distribution, Metabolism, Elimination & Toxicity

Biotransformation

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.

Protein Binding

21% bound to plasma proteins over the therapeutic dose range.

Absorption

Although well absorbed orally, naltrexone is subject to significant first pass metabolism with oral bioavailability estimates ranging from 5 to 40%.

Half Life

4 hours for naltrexone and 13 hours for the active metabolite 6 beta-naltrexol.

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.

Chemical Properties

Chemical Formula:

C₂₀H₂₃NO₄

SMILES Code:

c1cc(c2c3c1C[C@@H]4[C@]5([C@]3(CCN4CC6CC6)[C@@H](O2)C(=O)CC5)O)O

(Format: OpenEye Isomeric)

Molecular Weight ( average / monoisotopic )

341.4009 / 341.1627

Curated Annotations ()

1. rs1799971 at chr6:154402490 in OPRM1
   This variant is associated with increased receptor affinity, alcohol-induced euphoria, and risk for alcohol use disorders. Alcoholic subjects with an Asp40 allele tend to have better clinical outcomes ( increased percentage of days abstinent and decreased percentage of heavy drinking days) when treated with naltrexone for alcoholism compared to those with the Asn40/Asn40 genotype.

   Variant Name:

   OPRM1: A118G; Asn40Asp

   Related Drugs:

   ethanol, naltrexone

   Related Diseases:

   Alcoholism

   Evidence:

   PMID:15525999
   PMID:15608594
   PMID:17339526
   PMID:18250251
   PMID:8072460
   

Curated Information

The following genes are in curated knowledge about this drug.

	Gene	Relationship	Evidence
	CYP2D6	PK    GN	Publications
	OPRM1	CO PD       GN	Publications, Variants

Non-Curated Information

A list of non-curated publications that mention this drug along with other genes is available.

Drug Targets

• OPRM1
• TNF
• OPRD1
• OPRK1

Non-Curated Information

A list of non-curated publications that mention this drug along with other drugs is available.

Drug Interactions

Curated Information

The following diseases are in curated knowledge about this drug.

	Disease	Relationship	Evidence
	Alcohol-Related Disorders	CO PD       GN	Publications
	Alcoholism	CO PD       GN	Publications, Variants

Non-Curated Information

A list of non-curated publications that mention this drug along with other diseases is available.

Additional Datasets

These datasets are minimally curated and are sorted alphabetically by title.

1. The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease

LinkOuts

Common Searches

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Non-Curated Publications

A list of non-curated publications that mention this drug is available.