Naltrexone

DEA NFLIS-Drug Category -> Narcotics

Pharmaceuticals -> Listed in ZINC15

log Kow = 1.92

0.7

1.12

Solubility of 100 mg/mL in water at 25 °C /Naltrexone hydrochloride/

Insoluble in water

Soluble in ethanol

3.07e+00 g/L

Breast Feeding; Lactation; Milk, Human; Alcohol Deterrents; Narcotic Antagonists

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Pharmaceuticals

Medicines for alcohol use disorders

Hazardous decomposition products formed under fire conditions - Carbon oxides, nitrogen oxides (NOx), hydrogen chloride gas. /Naltrexone hydrochloride/

When heated to decomposition it emits toxic fumes of /nitrogen oxides/.

168-170 °C

169 °C

Crystals from methanol. MP: 274-276 °C /Naltrexone hydrochloride/

169 - 170 °C; 274 - 276 °C (hydrochloride salt)

Stable under recommended storage conditions. /Naltrexone hydrochloride/

/Naltrexone/ has been mixed with juices and syrups to mask the bitter taste and was stable for 60-90 days.

183.5 Ų [M+K]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

176.5 Ų [M+H]+ [CCS Type: TW; Method: Major Mix IMS/Tof Calibration Kit (Waters)]

177.6 Ų [M+H]+ [CCS Type: DT; Method: single field calibrated]

Danger

H302 (50%): Harmful if swallowed [Warning Acute toxicity, oral]

P203, P233, P260, P261, P264, P270, P271, P272, P273, P280, P284, P301+P317, P302+P352, P304+P340, P317, P318, P321, P330, P333+P317, P342+P316, P362+P364, P391, P403, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 76 reports by companies from 8 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Warning

H302: Harmful if swallowed [Warning Acute toxicity, oral]

Naltrexone. ... Indications for use. As an antagonist to carfentanil citrate immobilization in free-ranging or confined elk and moose (Cervidae). ... Federal law restricts this drug to use by or on the order of a licensed veterinarian.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including naltrexone, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including naltrexone hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Naltrexone hydrochloride/

The Generic Animal Drug and Patent Restoration act requires that each sponsor of an approved animal drug must submit to the FDA certain information regarding patents held for the animal drug or its method of use. The Act requires that this information, as well as a list of all animal drug products approved for safety and effectiveness, be made available to the public. Naltrexone hydrochloride is included on this list. /Naltrexone hydrochloride/

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide. /Naltrexone hydrochloride/

Advice for firefighters: Wear self-contained breathing apparatus for firefighting if necessary. /Naltrexone hydrochloride/

Keep container tightly closed in a dry and well-ventilated place. Recommended storage temperature 2 - 8 °C. Light sensitive. Keep in a dry place. /Naltrexone hydrochloride/

Naltrexone hydrochloride tablets should be stored in well-closed containers at 15-30 °C.

The entire dose pack containing naltrexone for extended-release injectable suspension should be refrigerated at 2-8 °C; the dose pack can be stored at room temperature (ie, room temperatures not exceeding 25 °C) for up to 7 days. Storage at temperatures above 25 °C or freezing should be avoided.

Store in a tightly sealed container, protected from light, and at room temperature.

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Avoid breathing dust. Environmental precautions: Do not let product enter drains. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal. /Naltrexone hydrochloride/

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material. Dissolve or mix the material with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber; Contaminated packaging: Dispose of as unused product. /Naltrexone hydrochloride/

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Avoid breathing dust. Environmental precautions: Do not let product enter drains. /Naltrexone hydrochloride/

Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed. /Naltrexone hydrochloride/

Appropriate engineering controls: Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday. /Naltrexone hydrochloride/

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands. /Naltrexone hydrochloride/

SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

Eye/face protection: Safety glasses with side-shields conforming to EN166. Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU). /Naltrexone hydrochloride/

Skin protection: Handle with gloves. /Naltrexone hydrochloride/

Body Protection: Complete suit protecting against chemicals. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace. /Naltrexone hydrochloride/

Respiratory protection: For nuisance exposures use type P95 (US) or type P1 (EU EN 143) particle respirator. For higher level protection use type OV/AG/P99 (US) or type ABEK-P2 (EU EN 143) respirator cartridges. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). /Naltrexone hydrochloride/

Naltrexone may increase the CNS effects of yohimbine (anxiety, tremors, nausea, palpitations) and increase plasma cortisol levels.

Naltrexone is a clinically approved medication for alcoholism. We aimed to investigate the effectiveness of naltrexone co-administered with cocaine and the association of these substances with immediate-early gene expression in the rat prefrontal cortex. We used chronic operant ethanol self-administration and oral treatments prescribed for alcoholism and available in pharmacies to maximize the predictive validity in humans. We performed real-time PCR analysis to determine gene expression levels in the prefrontal cortex. Only the highest dose of naltrexone (1, 3, and 10 mg/kg, p.o.) reduced the response to ethanol. Cocaine increased ethanol self-administration in a dose-dependent manner (2.5, 10, 20 mg/kg, i.p.) and reversed the naltrexone-induced reduction. Naltrexone failed to prevent the cocaine-induced increase in locomotor activity observed in these animals. Chronic self-administration of ethanol reduced the expression of the C-fos gene 4- to 12-fold and increased expression of the COX-2 (up to 4-fold) and Homer1a genes in the rat prefrontal cortex. Chronic ethanol self-administration is prevented by naltrexone, but cocaine fully reverses this effect. This result suggests that cocaine may overcome naltrexone's effectiveness as a treatment for alcoholism. The ethanol-induced reduction in C-fos gene expression in the prefrontal cortex reveals an abnormal activity of these neurons, which may be relevant in the compulsive consumption of ethanol, the control of reward-related areas and the behavioral phenotype of ethanol addiction.

In appetite research, drugs frequently progress to clinical trials on the basis of outcome (reduced food intake/body weight gain) with insufficient attention to process (behavioral analysis). Although bupropion and naltrexone (alone and in combination) reduce food consumption in rodents and humans, their effects on behavior during feeding tests have not been thoroughly investigated. This study aimed to assess the behavioral specificity of anorectic responses to bupropion, naltrexone and their combination. Video analysis was employed to characterize the behavioral effects of acute systemic treatment with bupropion (10.0-40.0 mg/kg), naltrexone (0.1-3.0 mg/kg) and combined bupropion (20 mg/kg) plus naltrexone (0.1-1.0 mg/kg) in non-deprived male rats exposed for 1 hr to palatable mash. Particular attention was paid to the behavioral satiety sequence (BSS). In experiment 1, the anorectic response to 40 mg/kg bupropion was associated with significant psychomotor stimulation and a complete disruption of the BSS. In experiment 2, the anorectic response to 3 mg/kg naltrexone was associated with an accelerated but otherwise normal BSS. In experiment 3, the co-administration of 20 mg/kg bupropion and naltrexone (0.1 and 1.0 mg/kg) not only produced an additive anorectic profile (including a reduced rate of eating), but the addition of the opioid receptor antagonist also concurrently attenuated the psychomotor stimulant response to the atypical antidepressant. Low-dose co-treatment with naltrexone and bupropion produces a stronger suppression of appetite than that seen with either agent alone and has the additional advantage of reducing some of the unwanted effects of bupropion.

Opioid antagonists (e.g., naltrexone) and positive modulators of gamma-aminobutyric-acidA (GABAA) receptors (e.g., alprazolam) modestly attenuate the abuse-related effects of stimulants like amphetamine. The use of higher doses to achieve greater efficacy is precluded by side effects. Combining naltrexone and alprazolam might safely maximize efficacy while avoiding the untoward effects of the constituent compounds. The present pilot study tested the hypothesis that acute pretreatment with the combination of naltrexone and alprazolam would not produce clinically problematic physiological effects or negative subjective effects and would reduce the positive subjective effects of d-amphetamine to a greater extent than the constituent drugs alone. Eight nontreatment-seeking, stimulant-using individuals completed an outpatient experiment in which oral d-amphetamine (0, 15, and 30 mg) was administered following acute pretreatment with naltrexone (0 and 50 mg) and alprazolam (0 and 0.5 mg). Subjective effects, psychomotor task performance, and physiological measures were collected. Oral d-amphetamine produced prototypical physiological and stimulant-like positive subjective effects (e.g., VAS ratings of Active/Alert/Energetic, Good Effect, and High). Pretreatment with naltrexone, alprazolam, and their combination did not produce clinically problematic acute physiological effects or negative subjective effects. Naltrexone and alprazolam each significantly attenuated some of the subjective effects of d-amphetamine. The combination attenuated a greater number of subjective effects than the constituent drugs alone. The present results support the continued evaluation of an opioid receptor antagonist combined with a GABAA-positive modulator using more clinically relevant experimental conditions like examining the effect of chronic dosing with these drugs on methamphetamine self-administration.

For more Interactions (Complete) data for Naltrexone (7 total), please visit the HSDB record page.

Tolerance can develop, in which the person needs larger doses to achieve the desired effect; this can lead to overdose and death. Accidents or injury can also occur due to the side effects of loss of coordination, slowed reaction time, sleepiness and impaired judgment. Drugs in this category have a high potential for physical and psychological dependence.

Naltrexone therapy is typically given to patients with a high background rate of liver disease (injection drug use or alcoholism) and has been associated with variable rates of serum enzyme elevations (0% to 50%), values above 3 times the upper limit of normal occurring in approximately 1% of patients and occasionally leading to drug discontinuation. However, several studies have shown that the rate of ALT elevations during naltrexone therapy is similar to that with placebo. Most serum aminotransferase elevations during naltrexone therapy are mild and self-limiting, resolving even with continuation of therapy. While several rare instances of acute, clinically apparent liver disease have been reported in patients taking naltrexone, the role of the medication in the liver injury has not always been clear and there has been no clear description of the clinical features of the injury. Thus, while often considered hepatotoxic, naltrexone has not been definitively linked to cases of clinically apparent liver injury.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1040(SRC), determined from a structure estimation method(2), indicates that naltrexone is expected to have low mobility in soil(SRC). The pKa values of naltrexone are 8.38 and 9.93(3), indicating that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization of the cation from moist soil is not expected because cations do not volatilize(SRC). Naltrexone is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.1X10-11 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2017).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1040(SRC), determined from a structure estimation method(2), indicates that naltrexone is expected to adsorb to suspended solids and sediment(SRC). The pKa values of 8.38 and 9.93(3) indicate naltrexone will exist almost entirely in the cation form at pH values of 5 to 9 and, therefore, volatilization from water surfaces is not expected to be an important fate process(SRC). Naltrexone is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(4). According to a classification scheme(5), an estimated BCF of 9(SRC), from its log Kow of 1.92(6) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low. Biodegradation data in water were not available(SRC, 2017).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), naltrexone, which has an estimated vapor pressure of 3.1X10-11 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase naltrexone may be removed from the air by wet or dry deposition(SRC). Naltrexone does not contain chromophores that absorb at wavelengths >290 nm(3) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).

IDENTIFICATION AND USE: Naltrexone is a narcotic antagonist. It is also used in the treatment of alcoholism. Naltrexone hydrochloride is designated an orphan drug by the US Food and Drug Administration (FDA) in the maintenance of opiate cessation. HUMAN STUDIES: Naltrexone competes for opiate receptors and displaces opioid drugs from these receptors, thus reversing their effects. It is capable of antagonizing all opiate receptors. The mechanism of action of naltrexone in alcohol dependence is not known. Patients receiving 800 mg of naltrexone hydrochloride daily for up to 1 week in one study showed no evidence of toxicity. However, lower dosages reportedly have been hepatotoxic in some patients. No serious adverse effects were observed following administration of single naltrexone doses of up to 784 mg (as the extended-release im injection) in several healthy individuals. Naltrexone was not associated with the high rates of neonatal mortality or congenital anomalies seen in methadone-exposed neonates. Mutagenic changes and chromosomal damage have occurred in vitro in human lymphocytes exposed to naltrexone. ANIMAL STUDIES: Acute toxicity from naltrexone in mice, rats, and dogs resulted in death secondary to tonic-clonic seizures and/or respiratory failure. Weight loss occurred in monkeys following subcutaneous administration of 100 mg/kg doses, and prostration, seizures, and death occurred following subcutaneous administration of 300 mg/kg doses. Hypoactivity, salivation, and emesis occurred in monkeys following oral administration of 1 g/kg doses, and seizures and death occurred following oral administration of 3 g/kg doses. Bradycardia has occurred following iv naltrexone hydrochloride doses of 5-80 ug/kg in unanesthetized dogs, however, respiratory rate, blood pressure, arterial blood gases, and EEG remained unchanged throughout the dose range. Within 20 minutes of 1 mg/kg iv doses in cats, total brain oxygen consumption decreased by about 48% and blood flow to the entire brain and the pons decreased by about 40%. In a 2-year study of the carcinogenic potential of naltrexone, there was an increase in the frequency of mesotheliomas in male rats and tumors of vascular origin in both male and female rats. No evidence of carcinogenicity was observed in several other 2-year studies in mice or rats receiving naltrexone dosages of 30 or 100 mg/kg daily. Naltrexone dosages of 100 mg/kg daily in rats produced an increase in pseudopregnancy and a decrease in the pregnancy rate in mated rats. Naltrexone did not exhibit clastogenicity in an in-vivo mouse micronucleus assay. No evidence of genotoxic potential was observed in a range of other in-vitro tests, including assays for gene mutation in bacteria, yeast, or in a second mammalian cell line, a chromosomal aberration assay. However, mutagenic changes and chromosomal damage have occurred in vitro in Chinese hamster ovarian cells, in the Drosophila recessive lethal assay, and in nonspecific DNA repair tests with Escherichia coli and WI-38 cells. ECOTOXICITY STUDIES: In order to evaluate the influence of the season (the stage of gonad maturity) on the modulatory role of endogenous opioid peptides in LH secretion in fish, sexually mature male carp (Cyprinus carpio L.) were intravenously injected with naltrexone-opioid receptor antagonist (5 or 50 ug/kg) in the period of natural spawning (June) or gonad recrudescence (December). In June, naltrexone significantly lowered LH levels in comparison to saline injected males. In December, there were no differences between saline and naltrexone-injected carps.

There is limited data on naltrexone hydrochloride overdosage in humans. In one study, patients who received 800 mg daily naltrexone hydrochloride for seven days reported no symptoms of toxicity. Cases of hepatitis and liver dysfunction have been observed; transient asymptomatic hepatic transaminase elevations may also occur. Hepatotoxicity is dose-dependent. Reports exist of depression, suicidal ideation, and suicidal attempts. Monitor the patient for symptoms of depression or suicidality. In animal studies, high doses of naltrexone (>1000 mg/kg) produced salivation, reduced activity, depression, tremors, and convulsions. Death in animals was due to clonic-tonic convulsions and respiratory failure.

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, kappa, and delta receptors in the CNS, with the highest affintiy for the mu 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-beta-naltrexol, is also an opiate antagonist and may contribute to the antagonistic activity of the drug.

/AQUATIC SPECIES/ In order to evaluate the influence of the season (the stage of gonad maturity) on the modulatory role of endogenous opioid peptides in LH secretion in fish, sexually mature male carp (Cyprinus carpio L.) were intravenously injected with naltrexone-opioid receptor antagonist (5 or 50 ug/kg) in the period of natural spawning (June) or gonad recrudescence (December). Moreover, the possible involvement of the dopaminergic system was studied in fish pre-treated with pimozide (dopamine receptor antagonist) and in intact fish. Blood samples were taken every minute, up to 10 min after naltrexone injection. In June, naltrexone significantly lowered LH levels in comparison to saline injected males. In December, there were no differences between saline and naltrexone-injected carps. In fish pre-treated with pimozide, neither in June nor in December were any significant differences in LH levels between control group and the groups injected with naltrexone found. The results showed that, in male carp, LH secretion under the influence of naltrexone depends on the stage of gonad maturity what suggests that the feedback of gonadal steroids on LH release could be mediated by the endogenous opioids. The role of dopamine in these processes is also discussed.

Naltrexone. ... Indications for use. As an antagonist to carfentanil citrate immobilization in free-ranging or confined elk and moose (Cervidae). ... Federal law restricts this drug to use by or on the order of a licensed veterinarian.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including naltrexone, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including naltrexone hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Naltrexone hydrochloride/

The Generic Animal Drug and Patent Restoration act requires that each sponsor of an approved animal drug must submit to the FDA certain information regarding patents held for the animal drug or its method of use. The Act requires that this information, as well as a list of all animal drug products approved for safety and effectiveness, be made available to the public. Naltrexone hydrochloride is included on this list. /Naltrexone hydrochloride/

N - Nervous system

QN - Nervous system

N07BB04

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.

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.

Naltrexone competes for opiate receptors and displaces opioid drugs from these receptors, thus reversing their effects. It is capable of antagonizing all opiate receptors.

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

Plasma concentrations of naltrexone and 6-beta-naltrexol, the major metabolite, appear to decline in a biphasic manner during the first 24 hours following a single oral dose or during chronic administration of the drug. Following oral administration of single or multiple doses of naltrexone hydrochloride, the plasma half-lives of naltrexone and 6-beta-naltrexol in the initial phase (t1/2 alpha) average 1.1-3.9 and 2.3-3.1 hours, respectively, and the plasma half-lives in the terminal phase (t1/2 beta) average 9.7-10.3 and 11.4-16.8 hours, respectively. Plasma concentrations of naltrexone and 6-beta-naltrexol have also been reported to decline in a triphasic manner following oral administration, with a terminal elimination half-life after the first 24 hours of 96 hours for naltrexone and 18 hours for 6-beta-naltrexol, possibly resulting from initial distribution into body tissues and subsequent redistribution into systemic circulation.

Pharmacokinetics of naltrexone hydrochloride (NTX) and naltrexone glucuronide was studied in the dog using HPLC-electrochemical detection with naloxone as internal standard. After iv 5 mg or po 10 mg NTX, ... the elimination half-lives of NTX were 78 +/- 6 min and 74 +/- 6 min, respectively. ... The major metabolite of NTX in dog plasma was beta-glucuronidase-hydrolyzable conjugate. Dosing NTX intravenously and orally, ... the elimination half-lives of the glucuronide from plasma were 3.4 hr and 12.6 hr, respectively.

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.

Naltrexone is metabolized in the liver principally by reduction of the 6-keto group of naltrexone to 6-beta-naltrexol (6-beta-hydroxynaltrexone). Naltrexone also undergoes metabolism by catechol-O-methyl transferase (COMT) to form 2-hydroxy-3-methoxy-6-beta-naltrexol (HMN) and 2-hydroxy-3-methoxynaltrexone. Several minor metabolites have also been identified, including noroxymorphone and 3-methoxy-6-beta-naltrexol. Because oral but not im administration of naltrexone results in substantial first-pass hepatic metabolism of the drug, 6-beta-naltrexol concentrations following im administration are substantially lower than concentrations of the metabolite obtained following oral administration. Naltrexone does not appear to inhibit or induce its own metabolism following chronic administration. Cytochrome P-450 (CYP) isoenzymes are not involved in the metabolism of naltrexone. Naltrexone and its metabolites undergo conjugation with glucuronic acid. The major fraction of total drug and metabolites in both plasma and urine consists of conjugated metabolites. The drug and its metabolites may undergo enterohepatic circulation.

Metabolites of naltrexone may contribute to the opiate antagonist activity of the drug. Like naltrexone, 6-beta-naltrexol is an essentially pure opiate antagonist, with a potency of 6-8% that of naltrexone in precipitating withdrawal symptoms in dogs physically dependent on morphine and 1.25-2% that of naltrexone in mice. Because of its weak affinity for opiate receptors, 2-hydroxy-3-methoxy-6-beta-naltrexol (HMN) may not contribute appreciably to the opiate antagonist activity of naltrexone; however, the in vivo opiate antagonist activity of HMN or 2-hydroxy-3-methoxynaltrexone has not been studied. Noroxymorphone, a minor metabolite of naltrexone, is a potent opiate agonist and may be responsible for the agonist activity (eg, miosis) that occurs infrequently in individuals receiving naltrexone.

Naltrexone and its metabolites (unconjugated and conjugated) are excreted principally in urine via glomerular filtration; 6-beta-naltrexol, conjugated 6-beta-naltrexol, and conjugated naltrexone are also excreted via tubular secretion. Naltrexone may also undergo partial reabsorption by the renal tubules. Following single- or multiple-dose oral administration of naltrexone hydrochloride, respectively, approximately 38-60 or 70% of a dose has been recovered in urine, principally as 6-beta-naltrexol (conjugated and unconjugated). Most urinary excretion of naltrexone occurs within the first 4 hours after oral administration. Less than 2% of an orally administered dose is excreted unchanged in urine within 24 hours. Approximately 5-10, 19-35, 7-16, 3.5-4.6, and 0.45% of an oral dose are excreted in urine as conjugated naltrexone, 6-beta-naltrexol, conjugated 6-beta-naltrexol, 2-hydroxy-3-methoxy-6-beta-naltrexol (HMN), and 2-hydroxy-3-methoxynaltrexone, respectively, within 24 hours. Less than 5% of a dose is excreted in feces, principally as 6-beta-naltrexol, within 24 hours following single- or multiple-dose oral administration of the drug. Following oral administration of 50 mg of radiolabeled naltrexone in one patient, approximately 93% of the radiolabeled dose was excreted within 133 hours; about 79 and 14% were excreted in urine and feces, respectively.

Following im administration of naltrexone extended-release injection, the half-life of naltrexone and 6-beta-naltrexol is 5-10 days.

For more Metabolism/Metabolites (Complete) data for Naltrexone (6 total), please visit the HSDB record page.

5S6W795CQM

NALTREXONE

Established Pharmacologic Class [EPC] - Opioid Antagonist

Mechanisms of Action [MoA] - Opioid Antagonists

Naltrexone is an Opioid Antagonist. The mechanism of action of naltrexone is as an Opioid Antagonist.

Substances interfering with the metabolism of ethyl alcohol, causing unpleasant side effects thought to discourage the drinking of alcoholic beverages. Alcohol deterrents are used in the treatment of alcoholism.

Agents inhibiting the effect of narcotics on the central nervous system.

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

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.

1350 L [intravenous administration]

~ 3.5 L/min [after IV administration]

Naltrexone hydrochloride is rapidly and almost completely (about 96%) absorbed from the GI tract following oral administration, but the drug undergoes extensive first-pass metabolism in the liver. Only 5-40% of an orally administered dose reaches systemic circulation unchanged. Considerable interindividual variation in absorption of the drug during the first 24 hours after a single dose has been reported. The bioavailability of naltrexone hydrochloride tablets is reportedly similar to that of an oral solution of the drug (not commercially available in the US).

Peak plasma concentrations of naltrexone and 6-beta-naltrexol (the major metabolite of naltrexone) usually occur within 1 hour following oral administration of the tablets and 0.6 hours following oral administration of the solution. Because orally administered naltrexone undergoes substantial first-pass metabolism, plasma concentrations of 6-beta-naltrexol following oral administration are substantially higher than corresponding concentrations of naltrexone. Following oral administration, the area under the serum concentration-time curve (AUC) for 6-beta-naltrexol is 10-30 times greater than the AUC for naltrexone. Following single- or multiple-dose (i.e., once daily) oral administration of naltrexone hydrochloride 50 mg in healthy individuals, peak plasma concentrations of naltrexone and 6-beta-naltrexol averaged 10.6-13.7 and 109-139 ng/mL, respectively.

Narcotic Antagonists

MEDICATION

Use (kg; approx.) in Germany (2009): >10

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.

17-but-3-enyl-4,5alpha-epoxy-3,14-dihydroxymorphinan-6-one

17-butyl-4,5alpha-epoxy-3,14-dihydroxymorphinan-6-one

3-(cyclopropylmethoxy)-17-(cyclopropylmethyl)-4,5alpha-epoxy-14-hydroxymorphinan-6-one

17-(cyclopropylmethyl)-4-5alpha-epoxy-3,10alpha,14-trihydroxymorphinan-6-one

For more Impurities (Complete) data for Naltrexone (10 total), please visit the HSDB record page.

Table: Naltrexone Preparations [Table#6238]

Table: Naltrexone Hydrochloride Preparations [Table#6239]

Commercially available naltrexone for extended-release injectable suspension (Vivitrol) contains naltrexone incorporated into microspheres composed of polylactide co-glycolide, a biodegradable polymer matrix. Following reconstitution with the diluent provided by the manufacturer, naltrexone suspension is milky white, does not contain clumps, and moves freely down the wall of the vial. The diluent provided by the manufacturer provides an appropriate vehicle for reconstitution and delivery of the drug and contains carboxymethylcellulose sodium, polysorbate 20, and sodium chloride in sterile water for injection.

Celupan /Naltrexone hydrochloride/

For more Formulations/Preparations (Complete) data for Naltrexone (6 total), please visit the HSDB record page.

Approved in the US for the treatment of alcohol abuse.

Subcutaneous (investigational): Because of notoriously poor compliance, studies are in progress utilizing a biodegradable bead containing naltrexone that would require subcutaneous implantation only once a month.