Absorption, Distribution and Excretion
Nalmefone is rapidly absorbed after a single oral dose of 18.06 mg, with an absolute oral bioavailability of 41%. The Cmax is 16.5 ng/mL, and the Tmax is approximately 1.5 hours. The exposure (AUC) is 131 ng·h/mL. A high-fat diet may increase AUC by 30%, Cmax by 50%, and delay Tmax by 30 minutes; however, this is unlikely to be clinically significant. Following intravenous administration of 0.5 mg to 2 mg of nalmefone, its pharmacokinetics are dose-proportional. The Tmax after intramuscular injection is 2.3 ± 1.1 hours, and after subcutaneous injection, it is 1.5 ± 1.2 hours. In emergency situations, therapeutic plasma concentrations can be reached within 5 to 15 minutes after a 1 mg dose. Absorption rates after intramuscular and subcutaneous injection vary among individuals. The primary route of elimination for nalmefone and its metabolites is renal excretion. Approximately 54% of the total dose is excreted in the urine as nalmefone 3-O-glucuronide. Less than 3% of the dose is excreted as nalmefene or other metabolites. Approximately 17% of the dose is excreted in feces. Nalmefene is rapidly distributed after a 1 mg parenteral dose. The central volume of distribution (V_c) and steady-state volume of distribution (V_dss) are 3.9 ± 1.1 L/kg and 8.6 ± 1.7 L/kg, respectively. Nalmefene readily crosses the blood-brain barrier. The oral clearance (CL/F) of nalmefene is estimated to be 169 L/h. Following intravenous administration of 1 mg nalmefene, the systemic clearance is 0.8 ± 0.2 L/hr/kg, and the renal clearance is 0.08 ± 0.04 L/hr/kg. In 12 male volunteers, the bioavailability of nalmefene administered intramuscularly or subcutaneously was comparable to that administered intravenously. The relative bioavailability for intramuscular and subcutaneous injections was 101.5% ± 8.1% (mean ± standard deviation) and 99.7% ± 6.9%, respectively. Nalmefene is primarily administered via intravenous bolus, but intramuscular or subcutaneous injection is also possible if intravenous access cannot be established. The time to peak plasma concentration of nalmefene after intramuscular injection is 2.3 ± 1.1 hours, and after subcutaneous injection it is 1.5 ± 1.2 hours; however, in emergency situations, therapeutic plasma concentrations can be reached within 5–15 minutes after a 1 mg dose. Due to the difference in absorption rates between intramuscular and subcutaneous injections, and the inability to adjust the dose based on efficacy, extra caution should be exercised if repeated administration via these routes is necessary. Nalmefene distributes rapidly after a 1 mg parenteral dose. In a brain receptor occupancy study, over 80% of brain opioid receptors were blocked within 5 minutes of 1 mg nalmefene administration. The central distribution volume (Vc) and steady-state distribution volume (Vdss) were 3.9 ± 1.1 L/kg and 8.6 ± 1.7 L/kg, respectively. Ultrafiltration studies of nalmefene showed that 45% (coefficient of variation 4.1%) of nalmefene was bound to plasma proteins within a concentration range of 0.1 to 2 μg/mL. In vitro distribution studies of nalmefene in human blood showed that 67% (CV 8.7%) was distributed in erythrocytes and 39% (CV 6.4%) in plasma. Within the nominal whole blood concentration range of 0.376 to 30 ng/mL, the whole blood to plasma concentration ratio was 1.3 (CV 6.6%). For more complete data on the absorption, distribution, and excretion of nalmefene (14 types), please visit the HSDB record page.

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Metabolism/Metabolites
Nalmefen is primarily metabolized in the liver, mainly through glucuronide conjugation, primarily mediated by UGT2B7 and UGT1A3, with UGT1A8 playing a minor role. The main metabolite is pharmacologically inactive nalmefen 3-O-glucuronide. Nalmefene is also metabolized to produce trace amounts of N-dealkylated metabolites, which have extremely low pharmacological activity. Nalmefene can be converted to nornalmefen via CYP3A4/5-mediated dealkylation. Nornalmefen can be further converted to nornalmefen 3-O-glucuronide and nornalmefen 3-sulfate, both of which are generally inactive. Nalmefene can also be converted to nalmefen 3-O-sulfate via CYP3A4/5-mediated sulfation, which retains some pharmacological activity. However, nalmefen 3-O-sulfate accounts for less than 10% of nalmefen in circulation; therefore, it is unlikely to be a major contributor to the pharmacological activity of nalmefen. Plasma concentration-time curves in some subjects indicated that nalmefene undergoes enterohepatic circulation. Nalmefene is primarily metabolized in the liver, conjugated with glucuronide, and excreted in the urine. Nalmefene is also metabolized into trace amounts of N-dealkylated metabolites. Nalmefene glucuronide is inactive, while the N-dealkylated metabolites have extremely low pharmacological activity. … Plasma concentration-time curves in some subjects indicated that nalmefene undergoes enterohepatic circulation. The distribution of nalmefene in rats and dogs was studied using in vitro and in vivo methods. In vitro metabolite profiling involved incubating nalmefene with liver microsomes and analyzing the biological fluids to determine the in vivo metabolite profile. Metabolite identification was performed using high-performance liquid chromatography (HPLC), co-chromatography with synthetic standards, or liquid chromatography-mass spectrometry (LC/MS). In rats, tissue distribution and plasma concentration-time data of metabolites were obtained after intravenous injection of nalmefene. Results showed that the major phase I metabolite of nalmefene during liver microsomal incubation was the N-dealkylated metabolite, nornalmefene. Quantitative metabolite production was higher in rats than in dogs. In vivo experiments indicated that nornalmefene glucuronide was the major metabolite in rat urine, while nalmefene glucuronide was the major metabolite in dog urine. Twenty-four hours after intravenous injection of 14C-nalmefene, over 90% of the radioactive dose was recovered in rat excrement and tissues, and no significant organ-specific radioactive retention was observed. Pharmacokinetic analysis of rat plasma metabolite data showed that the terminal half-lives of nalmefene and nornalmefene were comparable (approximately 1 hour). However, the Cmax and AUC of nornalmefene were ≤ 7% of the corresponding values for nalmefene. The terminal half-life after oral administration was approximately 12.5 hours. Following intravenous injection of 1 mg nalmefene in healthy adult male subjects, plasma concentrations exhibited a double exponential decrease and drug redistribution, with terminal elimination half-lives of 41 ± 34 minutes and 10.8 ± 5.2 hours, respectively. In normal males (19-32 years old), after intravenous injection of 1 mg nalmefene, plasma concentrations showed a double exponential decrease and drug redistribution, with terminal elimination half-lives of 41 ± 34 minutes and 10.8 ± 5.2 hours, respectively. In patients with impaired hepatic function, the elimination half-life increased from 10.2 ± 2.2 hours to 11.9 ± 2.0 hours. In patients with end-stage renal disease, the elimination half-life increased from 10.2 ± 2.2 hours in normal individuals to 26.1 ± 9.9 hours. The overall half-life ranged from 10.3 to 12.9 hours.

Hepatotoxicity
Nalmefene treatment has not been found to be associated with elevated serum enzymes or specific acute, clinically visible liver injury. Nalmefene is extensively metabolized in the liver, but primarily through glucuronidation rather than conversion to other metabolites. Opioid overdose patients often have coexisting chronic liver diseases, such as alcoholic liver disease, hepatitis B, or hepatitis C, but nalmefene treatment does not appear to exacerbate these conditions. Probability Score: E (Unlikely to be the cause of clinically visible liver injury). Drug Class: Opioid antagonists; See also: Drug abuse treatments. Other drugs in the same class: Naloxixol, Naloxone, Naltrexone. Pregnancy and Lactation Effects ◉ Overview of use during lactation There is currently no information regarding the use of nalmefene in breastfeeding women. If a mother needs to use nalmefene due to an opioid overdose, breastfeeding should be discontinued until the opioid is completely metabolized and eliminated from the body. Because nalmefene has limited oral bioavailability, its use by breastfeeding women may cause withdrawal symptoms in opioid-tolerant breastfed infants.
◉ Effects on breastfed infants
As of the revision date, no relevant published information was found.
◉ Effects on lactation and breast milk
Nalmefene increases serum prolactin levels in non-pregnant and non-lactating individuals. For mothers who have established lactation, prolactin levels may not affect their ability to breastfeed.

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Protein binding
Nalmefene has a protein binding rate between 30% and 45%. In vitro studies showed that 67% (coefficient of variation 8.7%) of nalmefene was distributed in erythrocytes and 39% (coefficient of variation 6.4%) in plasma. At nominal concentrations of nalmefene in whole blood ranging from 0.376 to 30 ng/mL, the whole blood to plasma concentration ratio was 1.3 (coefficient of variation 6.6%).

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Drug Interactions
Preclinical studies have shown that both flumazenil and nalmefene can induce seizures in animals. In rodent studies, the combined use of flumazenil and nalmefene resulted in fewer seizures than expected, and the expected outcome was based on the anticipated effects of each drug used alone. Based on these data, it is anticipated that the two drugs will not produce adverse interactions when taken concurrently, but physicians should still be aware of the potential risk of seizures caused by these drugs.

[1]. Nalmefene: a long-acting opioid antagonist. Clinical applications in emergency medicine. J Emerg Med. 1998 May-Jun;16(3):471-5.

[2]. Nalmefene for the management of alcohol dependence: review on its pharmacology, mechanism of action and meta-analysis on its clinical efficacy. Eur Neuropsychopharmacol. 2016 Dec;26(12):1941-1949.

Therapeutic Uses
Nasal opioid antagonist; neuroprotective agent; antipruritic agent. Nalmefene is indicated for the complete or partial reversal of the effects of opioids, including respiratory depression caused by natural or synthetic opioids. /Included on US product label/ Nalmefene is indicated for the treatment of known or suspected opioid overdose. /Included on US product label/ /Experimental Treatment:/ Pathological gambling is a disabling disorder affecting approximately 1-2% of adults, and currently, there are few evidence-based treatments available. The authors investigated the efficacy and tolerability of the opioid antagonist nalmefene in treating adult patients with pathological gambling. A 16-week randomized, dose-escalation, double-blind, placebo-controlled trial was conducted from March 2002 to April 2003 at 15 outpatient treatment centers in the United States. 207 patients meeting the DSM-IV diagnostic criteria for pathological gambling were randomized to receive nalmefene (25 mg, 50 mg, or 100 mg daily) or placebo. The primary efficacy endpoint (Yale-Brown Obsessive-Compulsive Scale for Pathological Gambling) scores were analyzed using a linear mixed-effects model. Estimated regression coefficients showed significant differences in scores on the Yale-Brown Obsessive-Compulsive Scale for Pathological Gambling compared to the placebo group between the 25 mg and 50 mg daily nalmefene groups. At the last evaluation, 59.2% of subjects receiving 25 mg daily nalmefene reported “significant improvement” or “very significant improvement,” compared to 34.0% of subjects receiving placebo. Adverse reactions included nausea, dizziness, and insomnia. Subjects receiving nalmefene experienced a statistically significant reduction in the severity of pathological gambling. Low-dose nalmefene (25 mg/day) appeared to be effective with fewer adverse events. Higher doses (50 mg/day and 100 mg/day) resulted in intolerable side effects.
Opioid antagonists have been shown to prevent fatal arrhythmias following coronary reperfusion. This study investigated the role of nalmefene, a long-acting and potent opioid antagonist, and its homologues in the prevention of reperfusion arrhythmias in dogs. Intravenous administration of 1 mg/kg nalmefene significantly reduced the incidence of reperfusion arrhythmias compared to the saline control group. Neither the quaternary ammonium analog N-methylnalmefene (which cannot cross the blood-brain barrier) nor the isomer (+) nalmefene, which lacks anti-opioid receptor activity, prevented reperfusion arrhythmias. During and after coronary artery occlusion, there were no differences in local myocardial blood flow profiles between the nalmefene and saline groups. Nalmefene prevents reperfusion-induced arrhythmias by blocking opioid receptors in the brain. Drug Warnings: Nalmefene is contraindicated in patients with known hypersensitivity to this product. Nalmefene, like other drugs in this class, is not a first-line treatment for respiratory failure. In most emergency situations, nalmefene treatment should be initiated after establishing a patent airway, providing respiratory support, administering oxygen, and establishing circulatory access, not before. Accidental overdose of long-acting opioids (such as methadone and levo-alpha-acetylmethadone (LAAM)) may lead to prolonged respiratory depression. Postoperative and overdose-related respiratory depression can be complex, involving the effects of anesthetics, neuromuscular blocking agents, and other medications. Although nalmefene lasts longer than naloxone at the fully reversible dose, physicians should be aware that respiratory depression can recur even if the initial response to nalmefene treatment appears good. Patients receiving nalmefene should be monitored until the physician deems there a reasonable risk of recurrence of respiratory depression. For more complete data on nalmefene (12 in total), please visit the HSDB records page.

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Pharmacodynamics
Nalmefene is an opioid antagonist without agonist activity. It works to prevent or reverse the effects of opioids, including respiratory depression, sedation, and hypotension. The duration of action of nalmefene is longer than that of naloxone, another opioid antagonist used to reverse opioid overdose. In a brain receptor occupancy study, 1 mg of nalmefene blocked more than 80% of brain opioid receptors within five minutes of administration. Nalmefene does not possess opioid agonist activity and is not associated with drug tolerance, physical dependence, or abuse potential. Nalmefene is not known to cause respiratory depression, psychiatric symptoms, or miosis. No pharmacological activity has been observed with nalmefene alone when not in combination with an opioid agonist. However, as with all opioid antagonists, nalmefene can cause acute withdrawal symptoms in opioid-dependent patients. These withdrawal symptoms should be treated with symptomatic and supportive care: attempting to overcome complete receptor blockade by administering large doses of opioids to patients receiving opioid antagonist therapy can lead to adverse respiratory and circulatory reactions.

C21H25NO3

339.43

339.183

55096-26-9

55096-26-9;58895-64-0 (HCl);1228646-70-5 (HCl dihydrate);1228646-72-7 (HCl hydrate);

5284594

White to off-white solid powder

188 - 190ºC

2.45

2

4

2

25

618

4

C=C1CC[C@]2([C@H]3CC4=C5[C@]2([C@H]1OC5=C(C=C4)O)CCN3CC6CC6)O

WJBLNOPPDWQMCH-MBPVOVBZSA-N

InChI=1S/C21H25NO3/c1-12-6-7-21(24)16-10-14-4-5-15(23)18-17(14)20(21,19(12)25-18)8-9-22(16)11-13-2-3-13/h4-5,13,16,19,23-24H,1-3,6-11H2/t16-,19+,20+,21-/m1/s1

(4R,4aS,7aS,12bS)-3-(cyclopropylmethyl)-7-methylidene-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,9-diol

ORF 11676; Nalmefeno; Nalmefene

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)