Absorption, Distribution and Excretion
Following oral administration, naloxixol is absorbed and reaches peak concentration (Cmax) within 2 hours. 68% is excreted in feces after oral administration; 16% is excreted in urine. The volume of distribution ranges from 968 to 2140 liters. Feces (68%), urine (16%). In healthy volunteers, the mean apparent volume of distribution (Vz/F) at the terminal phase ranged from 968 to 2140 liters across different dose groups and studies. Naloxixol has low plasma protein binding in humans (approximately 4.2%). A high-fat diet increases the extent and rate of naloxixol absorption. Cmax and AUC increase by approximately 30% and 45%, respectively. In clinical trials, naloxixol was taken on an empty stomach approximately 1 hour before the first meal in the morning. Following oral administration, Movantik is absorbed and reaches peak concentration (Cmax) within 2 hours. In most subjects, plasma concentrations of naloxixol showed a second peak approximately 0.4 to 3 hours after the first peak. Within the assessed dose range, both peak plasma concentrations and the area under the plasma concentration-time curve (AUC) increased in a dose-proportional or near-dose-proportional manner. Drug accumulation was minimal following multiple daily doses of naloxixol. /Breast Milk/ It is unclear whether Movantik enters human breast milk; however, naloxixol is present in rat milk and can be absorbed by lactating pups. For more complete data on the absorption, distribution, and excretion of naloxixol (a total of 8 metabolites), please visit the HSDB record page.

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Metabolism/Metabolites
Naloxixol is primarily metabolized via the CYP P450 3A4 enzyme system and undergoes enterohepatic circulation. In a human mass balance study, 6 metabolites were identified in plasma, urine, and feces. These metabolites are formed through N-dealkylation, O-demethylation, oxidation, and partial loss of the PEG chain. Human metabolic data indicate that no major metabolites exist. The activity of these metabolites on opioid receptors has not been determined. Naloxixol is primarily metabolized via the CYP3A enzyme system. In a human mass balance study, six metabolites were identified in plasma, urine, and feces. These metabolites are formed through N-dealkylation, O-demethylation, oxidation, and partial loss of the PEG chain. Human metabolic data indicate that no major metabolites exist. The activity of these metabolites on opioid receptors has not been determined. Biological half-life: 6–11 hours. In a clinical pharmacology study, the half-life of naloxixol at therapeutic doses was 6–11 hours. …The plasma pharmacokinetics of a single oral dose of 25 mg naloxixol were evaluated in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment and compared with healthy volunteers. Participants were matched for sex, age, and body mass index. The mean apparent terminal half-life was shorter in patients with mild hepatic impairment (9.6 hours) and moderate hepatic impairment (7.5 hours) than in healthy subjects (11.3 hours).

Toxicity Summary
Identification and Use: Naloxicillin is an opioid receptor antagonist indicated for the treatment of opioid-induced constipation in adult patients with chronic non-cancer pain. Human Exposure and Toxicity: In a clinical study of patients with opioid-induced constipation (OIC), daily administration of 50 mg (twice the recommended dose) for 4 weeks was associated with an increased incidence of gastrointestinal adverse reactions, such as abdominal pain, diarrhea, and nausea. These adverse reactions typically occurred within 1–2 days after administration. Animal Studies: In a 104-week mouse carcinogenicity study, naloxicillin was not tumorigenic at oral doses up to 100 mg/kg/day in male mice and up to 160 mg/kg/day in female mice (43 and 27 times the AUC at the maximum recommended human dose, respectively, for male and female mice, respectively). In a rat carcinogenicity study, naloxicillin was administered orally at doses of 40, 120, and 400 mg/kg/day for at least 93 weeks. Naloxixol did not increase the incidence of tumors in female rats. In male rats, an increased incidence of Leydig cell adenomas was observed at naloxixol doses up to 400 mg/kg/day (equivalent to 818 times the AUC at the maximum recommended human dose). The dose levels at which no increase in tumor incidence was observed were 120 mg/kg/day in male rats and 400 mg/kg/day in female rats (246 times and 1030 times the AUC at the maximum recommended human dose, respectively). Leydig cell tumors in rats are considered unlikely to be relevant to humans. During organogenesis, oral administration of naloxixol up to 750 mg/kg/day in rats (equivalent to 1452 times the AUC at the maximum recommended human dose) and up to 450 mg/kg/day in rabbits (equivalent to 409 times the AUC at the maximum recommended human dose) did not have adverse effects on embryo-fetal development. During organogenesis and lactation, oral administration of naloxixol up to 500 mg/kg/day (equivalent to 195 times the maximum recommended human dose based on body surface area) to rats did not have adverse effects on parturition or offspring. At oral doses up to 1000 mg/kg/day (more than 1000 times the AUC at the maximum recommended human dose), naloxixol had no effect on fertility or reproductive function in male and female rats. No genotoxicity of naloxixol was found in in vitro bacterial reverse mutation (Ames) assays, mouse lymphoma TK+/- mutation assays, or in vivo mouse micronucleus assays.
Hepatotoxicity
Naloxixol treatment was not associated with elevated serum enzymes or clinically significant liver injury. In pre-registration studies, less than 1% of treated patients experienced abnormal liver function, but these abnormalities were transient, mild, and asymptomatic. No cases of liver injury with jaundice or other symptoms have been reported. Since the approval and widespread use of naloxixol, there have been no published reports of hepatotoxicity.
Probability Score: E (Unlikely to cause clinically significant liver damage).

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Effects during pregnancy and lactation
◉ Overview of use during lactation
There is currently no information on whether naloxixol is excreted into breast milk. Because naloxixol may induce opioid withdrawal symptoms in breastfed infants, the manufacturer recommends against breastfeeding while receiving naloxixol treatment.
◉ Effects on breastfed infants
No published information found as of the revision date.
◉ Effects on lactation and breast milk
No published information found as of the revision date.

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Protein binding rate
~4.2%

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Interactions
Naloxixol is a pegylated, orally administered, peripherally acting μ-opioid receptor antagonist approved in the United States for the treatment of opioid-induced constipation in patients with non-cancer pain. Naloxixol is metabolized by CYP3A, and its role as a substrate for the P-glycoprotein (PGP) transporter limits its permeability to the central nervous system (CNS). This double-blind, randomized, two-part crossover study in healthy volunteers evaluated the effects of the CYP3A/PGP transporter inhibitor quinidine (600 mg, orally) on the pharmacokinetics and CNS distribution of naloxixol (25 mg, orally). Furthermore, the effects of quinidine on morphine (5 mg/70 kg, intravenously)-induced pupillary constriction and naloxixol exposure were assessed. Co-administration of quinidine with naloxixol increased naloxixol's AUC by 1.4-fold and Cmax by 2.5-fold, but did not antagonize morphine-induced pupillary constriction, indicating that PGP inhibition does not increase naloxixol's CNS permeability. Co-administration of morphine with either quinidine or placebo did not alter the pharmacokinetics of naloxixol. Conversely, the pharmacokinetics of morphine and its metabolites (in the presence of quinidine) are not affected by concomitant use with naloxixol. Naloxixol is safe and well-tolerated when used alone or in combination with quinidine, morphine, or both. The increased naloxixol exposure observed in the presence of quinidine is primarily attributed to quinidine's characteristics as a weak CYP3A inhibitor. This study evaluated the effects of CYP3A inhibition and induction on the pharmacokinetics, safety, and tolerability of naloxixol. Multiple open-label, non-randomized, fixed-sequence, 3-cycle, 3-treatment-group crossover studies were conducted in healthy volunteers to evaluate the efficacy of naloxixol (25 mg, orally) in the presence or absence of the inhibitor ketoconazole (400 mg, orally) and diltiazem extended-release tablets (240 mg, orally) or the inducer rifampin (600 mg, orally). Compared with Naloxegol alone, concomitant use with ketoconazole (12.9-fold) or diltiazem (3.4-fold) increased the area under the curve (AUCinf) of Naloxegol, while concomitant use with rifampin reduced it by 89%. Naloxegol is generally safe and well-tolerated, either alone or in combination with its corresponding CYP3A modulators; one subject withdrew from the study due to elevated liver enzymes caused by rifampin. Ketoconazole, diltiazem, and rifampin significantly affected Naloxegol exposure, indicating that it is a sensitive substrate for CYP3A4 in vivo. Concomitant use of St. John's wort may significantly reduce Naloxegol exposure; therefore, concomitant use should be avoided. Grapefruit juice is listed as a CYP3A4 inhibitor. Avoid consuming grapefruit or grapefruit juice while taking movantac. For more complete data on Naloxegol drug interactions (9 in total), please visit the HSDB record page.

[1] Am J Hosp Palliat Care . 2016 Nov;33(9):875-880.

[2] J Clin Pharmacol. 2016\nApr;56(4):508.

Naloxegol is an organic heteropentacyclic compound, a derivative of naloxone in which the keto group is replaced by a polyethylene glycol (PEG) group. It is used to treat opioid-induced constipation. It is a μ-opioid receptor antagonist and laxative. It belongs to the organic heteropentacyclic compounds, specifically the phenolic, aromatic ether, tertiary alcohol, and polyether classes. Its function is related to naloxone. It is derived from the hydride of morphine. Naloxegol, or "polyethylene glycolated naloxone," is a peripherally selective opioid receptor antagonist developed by AstraZeneca. It was approved by the U.S. Food and Drug Administration (FDA) in September 2014 for the treatment of opioid-induced constipation (OIC) in adults with chronic non-cancer pain. Naloxegol's advantage over the opioid antagonist naloxone lies in its PEGylated structure, which gives it high selectivity for peripheral opioid receptors and prevents it from crossing the blood-brain barrier into the central nervous system. Naloxegol is an opioid antagonist. Its mechanism of action is as an opioid antagonist. Naloxicol is a peripherally acting opioid antagonist used to treat constipation caused by long-term opioid use for non-cancer pain. No increase in serum enzymes or clinically significant liver injury has been observed with naloxicol during treatment. Naloxicol is a PEGylated derivative of naloxone, a peripherally acting μ-opioid receptor antagonist used to relieve opioid-induced symptoms. After administration, naloxicol binds to and blocks the action of μ-opioid receptors in the peripheral nervous system. This prevents peripheral opioid receptor activation and eliminates opioid-induced side effects such as opioid-induced constipation (OIC). The PEGylation of naloxone reduces its permeability across the blood-brain barrier (BBB), thus preventing the drug from interfering with the analgesic activity of opioid receptor agonists. See also: naloxicol oxalate (in salt form).

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Drug Indications
Indicated for the treatment of opioid-induced constipation (OIC) in adult patients with chronic non-cancer pain.

FDA Label

Indicated for the treatment of opioid-induced constipation (OIC) in adult patients who have an inadequate response to laxatives.

Treatment of opioid-induced constipationMechanism of Action
Naloxicol is a μ-opioid receptor antagonist. When administered at recommended doses, naloxicol acts as a peripheral μ-opioid receptor antagonist, acting on tissues such as the gastrointestinal tract to alleviate the constipating effect of opioids. Naloxicol has a selectivity for peripheral μ-receptors that is more than 6000 times higher than that of opioids, and its PEGylated form limits its action to the periphery, without affecting the analgesic mechanism of opioids in the central nervous system.
Naloxicol is a μ-opioid receptor antagonist.
At recommended doses, Naloxegol acts as a peripheral μ-opioid receptor antagonist, acting on tissues such as the gastrointestinal tract to alleviate the constipating effects of opioids. Naloxegol is a polyethylene glycol derivative of naloxone and a substrate of the P-glycoprotein transporter (P-gp). Furthermore, the presence of the polyethylene glycol (PEG) group in Naloxegol reduces its passive permeability compared to naloxone. Due to its P-gp substrate properties, Naloxegol's permeability across the blood-brain barrier is reduced and its efflux is increased; therefore, at recommended dose levels, its central nervous system permeability is expected to be negligible, thus limiting its interference with centrally mediated opioid analgesics.

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Therapeutic Use
Anesthetic Antagonist
/Clinical Trials/ ClinicalTrials.gov is a registry and results database that includes publicly and privately funded human clinical studies worldwide. This website is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each record on ClinicalTrials.gov provides summary information about the study protocol, including: the disease or condition; the intervention (e.g., the medical product, behavior, or procedure being studied); the study title, description, and design; participation requirements (eligibility criteria); the location of the study; contact information for the study location; and links to relevant information from other health websites, such as the NLM's MedlinePlus (which provides patient health information) and PubMed (which provides citations and abstracts of academic articles in the medical field). Naloxegol is indexed in this database. Movantik (Naloxegol) is indicated for the treatment of opioid-induced constipation (OIC) in adult patients with chronic non-cancer pain. /Included on US product label/

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Drug Warning
There have been reports of gastrointestinal perforation when using other peripherally acting opioid antagonists in patients with diseases that may be associated with localized or diffuse impairment of gastrointestinal wall structural integrity (e.g., peptic ulcer, Ogilvy syndrome, diverticulosis, invasive gastrointestinal malignancies, or peritoneal metastases). When using Movantik in patients with these diseases or other diseases that may impair gastrointestinal wall integrity (e.g., Crohn's disease), the overall risk-benefit ratio should be weighed. Monitor for severe, persistent, or worsening abdominal pain; if this symptom occurs, discontinue Movantik.
Patients treated with Movantik have experienced a range of symptoms consistent with opioid withdrawal symptoms, including excessive sweating, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Furthermore, clinical trials have observed that patients receiving methadone for pain treatment are more likely to experience gastrointestinal adverse reactions than those receiving other opioid treatments, which may be related to opioid withdrawal. Patients with impaired blood-brain barrier function may face a higher risk of opioid withdrawal or reduced analgesic effect. The overall risk-benefit ratio should be weighed when using Movantik in these patients. Opioid withdrawal symptoms should be monitored in these patients.
The effect of severe hepatic impairment (Child-Pugh C) on naloxixol pharmacokinetics has not been evaluated. Movantik should be avoided in patients with severe hepatic impairment, as the dosage for these patients has not been determined. No dose adjustment is required for patients with mild or moderate hepatic impairment.
Some subjects with creatinine clearance (CLcr) values < 60 mL/min (i.e., moderate, severe, or end-stage renal disease) have significantly higher systemic exposures to naloxixol than subjects with normal renal function. The reasons for these higher exposures are unclear. However, because higher systemic exposures correspond to a greater risk of adverse reactions, a starting dose of 12.5 mg once daily is recommended. No dose adjustment is required for patients with mild renal impairment.
For more complete (15) drug warnings for naloxixol, please visit the HSDB record page.

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Pharmacodynamics
Opioid use slows gastrointestinal motility and transit. Unlike many other opioid side effects, patients do not develop tolerance to these effects. Naloxicol antagonizes μ, δ, and κ opioid receptors, with the highest affinity for μ receptors. Naloxicol's antagonistic effect on gastrointestinal μ opioid receptors inhibits opioid-induced gastrointestinal transit time prolongation.

C₃₄H₅₃NO₁₁

651.78

651.362

854601-70-0

854601-70-0; 1354744-91-4 (oxalate);

56959087

Typically exists as solid at room temperature

1.801

2

12

24

46

899

5

O[C@]12[C@@H]3N(CC[C@@]41[C@H]([C@H](CC2)OCCOCCOCCOCCOCCOCCOCCOC)OC1C(=CC=C(C4=1)C3)O)CC=C

XNKCCCKFOQNXKV-ZRSCBOBOSA-N

InChI=1S/C34H53NO11/c1-3-9-35-10-8-33-30-26-4-5-27(36)31(30)46-32(33)28(6-7-34(33,37)29(35)25-26)45-24-23-44-22-21-43-20-19-42-18-17-41-16-15-40-14-13-39-12-11-38-2/h3-5,28-29,32,36-37H,1,6-25H2,2H3/t28-,29+,32-,33-,34+/m0/s1

(4R,4aS,7S,7aR,12bS)-7-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-3-prop-2-enyl-1,2,4,5,6,7,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,9-diol

AZ13337019 NKTR118NKTR-118 AZ-13337019PEGylated naloxol Movantik Moventig

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.)