Nalmefene

Preclinical studies have shown that both flumazenil and nalmefene can induce seizures in animals. The coadministration of both flumazenil and nalmefene produced fewer seizures than expected in a study in rodents, based on the expected effects of each drug alone. Based on these data, an adverse interaction from the coadministration of the two drugs is not expected, but physicians should remain aware of the potential risk of seizures from agents in these classes.

Therapy with nalmefene has not been linked to serum enzyme elevations or to idiosyncratic acute, clinically apparent liver injury. Nalmefene is extensively metabolized in the liver, but largely by glucuronidation rather than transformation to a different metabolite. Patients with opioid overdose often have underlying chronic liver diseases such as alcoholic liver disease, hepatitis B or C, but treatment with nalmefene does not appear to exacerbate those conditions.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1.4X10+4(SRC), determined from a structure estimation method(2), indicates that nalmefene is expected to be immobile in soil(SRC). The pKa of nalmefene hydrochloride is 7.63(3), indicating that this compound will exist partially in 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 nalmefene from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.8X10-16 atm-cu m/mole(SRC), using a fragment constant estimation method(5). Nalmefene is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 5.7X10-14 mm Hg at 25 °C(6). Biodegradation data in soil were not available(SRC, 2009).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1.4X10+4(SRC), determined from a structure estimation method(2), indicates that nalmefene is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 1.8X10-16 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 27(SRC), from an estimated log Kow of 2.66(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data in water are not available(SRC, 2009).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), nalmefene, which has an estimated vapor pressure of 5.7X10-14 mm Hg at 25 °C(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase nalmefene may be removed from the air by wet or dry deposition(SRC). Nalmefene 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).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of nalmefene can be estimated to be 1.4X10+4(SRC). According to a classification scheme(2), this estimated Koc value suggests that nalmefene is expected to be immobile in soil. The pKa of nalmefene hydrochloride is 7.63(3), indicating that this compound will exist partially in cation form in the environment, and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4).

/HUMAN EXPOSURE STUDIES/ A double blind randomized study of the pharmacology and abuse potential of nalmefene hydrochloride was conducted in 6 male volunteers (aged 28-43 yr) with histories of opiate abuse who received an oral capsule of 25, 50 and 100 mg oral nalmefene, an intramuscular injection of 15 and 30 mg morphine sulfate and placebo. Drowsiness or sleepiness was the most common drug effect reported after the administration of each treatment. Only morphine produced miosis and increased subject reported euphoria. Neither drug increased Addiction Research Inventory subscale scores measuring dysphoria or sedation or produced changes on the Profile of Mood States questionnaire. Adverse effects reported only after the administration of nalmefene included agitation/irritability and muscle tension. These effects did not appear to be dosage related. It was concluded that nalmefene did not produce typical morphine like effects and has no apparent abuse potential.

/SIGNS AND SYMPTOMS/ Intravenous doses of up to 24 mg of nalmefene, administered to healthy volunteers in the absence of opioid agonists, produced no serious adverse reactions, severe signs or symptoms, or clinically significant laboratory abnormalities. As with all opioid antagonists, use in patients physically dependent on opioids can result in precipitated withdrawal reactions that may result in symptoms that require medical attention. ... Administration of large amounts of opioids to patients receiving opioid antagonists in an attempt to overcome a full blockade has resulted in adverse respiratory and circulatory reactions.

/GENOTOXICITY/ nalmefene did exhibit a weak but significant clastogenic activity in the human lymphocyte metaphase assay in the absence but not in the presence of exogenous metabolic activation.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

Nalmefene

DILI Negative

Oral

DOI:10.1016/j.drudis.2019.09.022

An estimated BCF of 27 was calculated in fish for nalmefene(SRC), using an estimated log Kow of 2.66(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

The Henry's Law constant for nalmefene is estimated as 1.8X10-16 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that nalmefene is expected to be essentially nonvolatile from water surfaces(2). Nalmefene's Henry's Law constant indicates that volatilization from moist soil surfaces is not expected to occur(SRC). Nalmefene is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 5.7X10-14 mm Hg(3).

/LABORATORY ANIMALS: Acute Exposure/ The effects of the long-acting opioid antagonist, nalmefene [17-N-cyclopropylmethyl-3,14-beta-dihydroxy-4, 5-alpha-epoxy-6-methylene morphinan hydrochloride] on LH, T, and prolactin release in rhesus monkeys are unknown. The acute effects of nalmefene (0.01 and 0.10 mg/kg, IV) or placebo on LH, PRL, and T were studied, and samples were collected at 10-min intervals for 360 min to permit cluster analysis of pulsatile release patterns. LH increased significantly within 30 min after nalmefene, and remained significantly above baseline levels for 50 to 60 min (p < 0.05). Testosterone increased significantly within 70 to 80 min after nalmefene, and remained significantly above baseline for 60 min (p < 0.05). Although nalmefene antagonizes opioid agonists for 6-8 h, inhibitory feedback by testosterone appeared to limit the duration of its antagonism of endogenous opioid inhibition of LHRH and stimulation of LH. Nalmefene did not change LH or PRL pulse frequency or amplitude significantly in comparison to placebo administration.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Nalmefene is an orally available opioid receptor antagonist that has been shown to suppress appetite in humans, but its effects on chronic food intake and body weight remain unclear. Here, /investigators/ report that chronic (21-day) oral administration of nalmefene at 2 or 10 mg/kg/day in diet-induced obese (DIO) mice led to significant increases (9-11%) in cumulative food intake. Mice in the nalmefene-treated groups also gained body weight at a rate faster than the control. Body composition analysis showed that the extra body weight gains in the treated animals were mostly due to increased fat accumulation. Since acute nalmefene treatment showed a trend toward a decrease rather than an increase in food intake, it is possible that the orexigenic effect of chronic oral administration of nalmefene was caused by pharmacologically active metabolites rather than the drug itself. ...

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Reproduction studies have been performed in rats (up to 1200 mg/sq m/day) and rabbits (up to 2400 mg/sq m/day) by oral administration of nalmefene and in rabbits by intravenous administration up to 96 mg/sq m/day (114 times the human dose). There was no evidence of impaired fertility or harm to the fetus.

/GENOTOXICITY/ Nalmefene did not have mutagenic activity in the Ames test with five bacterial strains or the mouse lymphoma assay. Clastogenic activity was not observed in the mouse micronucleus test or in the cytogenic bone marrow assay in rats

Nalmefene is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(1). Nalmefene does not contain chromophores that absorb at wavelengths >290 nm(1) and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

Occupational exposure to nalmefene may occur through inhalation of dust during production, storage and transport, and dermal contact with this compound at workplaces where nalmefene is produced or used. Exposure to nalmefene among the general population may be limited to those administered the drug, an opioid antagonist. (SRC)

Is a pure opioid receptor antagonist ... used to reverse opioid intoxication and for the treatment of opioid dependence. The compound is in clinical development for the treatment of alcoholism, to support smoking cessation and to control pathological gambling.

Therapeutic Category: Narcotic antagonist

Therapeutic Category (Vet): Narcotic antagonist

MEDICATION

Nalmefene is synthesized by a Wittig reaction of naltrexone with triphenylmethylphosphonium bromide in DMSO under basic catalysis of NaH.

Preparation: J. Fishman, US 3814768 (1974 to M.J. Lewenstein)

Nalmetrene

REVEX