μ/κ-opioid receptor

Eluxadoline (ELD) is local-acting and exhibits diverse pharmacological effects, including m-OR and kappa opioid receptor agonists and delta opioid receptor antagonists. It exerts negligible oral bioavailability yet is officially approved by the United States Food and Drug Administration for IBS-D treatment. Due to its collective pharmacological properties, ELD significantly decreases the gut motility and reduces the probabilities of drug-induced constipation issues [1].

Eluxadoline (ELD), a recently approved drug, exhibits potential therapeutic effects in the management and treatment of IBS-D. However, its applications have been limited due to poor aqueous solubility, leading to a low dissolution rate and oral bioavailability. The current study's goals are to prepare ELD-loaded eudragit (EG) nanoparticles (ENPs) and to investigate the anti-diarrheal activity on rats. The prepared ELD-loaded EG-NPs (ENP1-ENP14) were optimized with the help of Box-Behnken Design Expert software. The developed formulation (ENP2) was optimized based on the particle size (286 ± 3.67 nm), PDI (0.263 ± 0.01), and zeta potential (31.8 ± 3.18 mV). The optimized formulation (ENP2) exhibited a sustained release behavior with maximum drug release and followed the Higuchi model. The chronic restraint stress (CRS) was successfully used to develop the IBS-D rat model, which led to increased defecation frequency. The in vivo studies revealed a significant reduction in defecation frequency and disease activity index by ENP2 compared with pure ELD. Thus, the results demonstrated that the developed eudragit-based polymeric nanoparticles can act as a potential approach for the effective delivery of eluxadoline through oral administration for irritable bowel syndrome diarrhea treatment [1].

A Box–Behnken response surface approach experimental design (Design-Expert® Software Version 13) was used to optimize the eluxadoline-loaded eudragit nanoparticles (ENPs) (3 factors, 3 levels). The independent variables selected were: the weight of the eudragit polymer (X1), %w/v, PVA (X2), and sonication time (X3), with their high, medium, and low levels for the preparation of 14 formulations, as shown in Table 1. Particle size (Y1), polydispersity index (Y2), and zeta potential (Y3) were the responses that were examined. Additionally, 3D response surface graphs were plotted to show how the specified factors affected the responses that were measured [1].

In Vitro Drug Release Studies [1]
In vitro drug release studies were performed to analyze the drug release behavior and the release mechanism of the optimized formulation. The analysis of pure ELD and the optimized formulation (ENP2) were determined using the dialysis membrane method. The pure ELD and ENP2 (5 mL) were loaded into the dialysis bag (Spectra/Por® Standard RC Tubing, MWCO 12 KDa) and tied at both ends. Then, the bags were dipped into a beaker containing a dissolution medium of pH 1.2 and pH 6.8 (200 mL), maintained at a temperature of 37 ± 2 °C, and kept under stirring at 100 rpm. At pre-estimated time intervals, 0.5 mL aliquots were withdrawn from each beaker and the sink condition was maintained by adding fresh media [31]. Furthermore, the aliquots were analyzed for drug content by the HPLC method and the percent drug release was calculated and plotted against the time. [30]. All the studies were performed in triplicate (n = 3). Additionally, the drug release mechanism of ELD from the optimized formulation at pH (1.2 and 6.8) was estimated by fitting the drug release results into different mathematical modeling, including zero order, first order, Higuchi, and Korsmeyer–Peppas kinetics models

In this study, the IBS rat model was induced by chronic restraint stress (CRS) as described by Lu et al. All rats were randomly divided into two groups (24 rats in the model group and 6 rats in the control group) after 7 days of adaptation. The rats in the model group were subjected to CRS using an elastic bandage to restrict the movement of the upper body and forelimbs and then anesthetized with ether. Their fore shoulders, upper forelimbs, and thoracic trunk were wrapped in elastic bandage for 2 h each day for 14 days to produce a steady and consistent amount of stimulation to restrict but not prevent movement. The control animals were anesthetized with ether but not restrained. [1]
Grouping and Administration
The rats were divided into five groups (n = 6) as follows:
Normal control group (NC): normal rats received saline (1 mL/kg).
IBS control group (IBS-C): CRS rats received saline (1 mL/kg).
Reference group (REF): CRS rats received loperamide (LRD) at 10 mg/kg.
Pure drug group (ELD-std): CRS rats received (20 mg/kg).
Formulation group (ENP2): CRS rats received (20 mg/kg).
Treatments were administered orally, started 6 h after IBS induction, and continued for 14 consecutive days. Body weights were recorded daily.

Absorption, Distribution and Excretion
The oral absorption of eluxadoline is poor - estimated to be 1.02%, this could be attributed to poor in vitro GI permeability, and its zwitterionic nature leading to a negatively charged molecule across the GI pH range.
82% excreted in feces, <1% excreted in urine.

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Metabolism / Metabolites
The metabolism of eluxadoline is currently unclear, however evidence suggests limited glucoronidation forms an acyl glucuronide metabolite that is then excreted into urine.

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Biological Half-Life
The mean plasma elimination half-life ranged from 3.7 hours to 6 hours.

Hepatotoxicity
In preregistration clinical trials, serum aminotransferase elevations were uncommon during eluxadoline therapy and in pooled analyses ALT elevations above 3 times the upper limit of normal occurred in 2% to 3% of eluxadoline- vs 1% of placebo-treated subjects. More detailed analysis found rare instances of marked ALT and AST elevations with eluxadoline therapy, not seen with placebo treatment. These more marked elevations were sometimes accompanied by abdominal pain and signs of sphincter of Oddi spasm (as can occur with opioid therapy) or pancreatitis. The abnormalities also arose largely in patients without a gallbladder or with a history of pancreatitis or hepato-biliary disease. Subsequent to the approval of eluxadoline and its more widescale use, over a hundred reports of pancreatitis (including 2 deaths) were reported to the Food and Drug Administration and eluxadoline was given a “black box” warning regarding its use in persons without a gallbladder. The clinical features of these reactions have not been well described, but they typically arise within the first few weeks of treatment with severe abdominal pain and vomiting sometimes accompanied by marked ALT and AST elevations with or without increases in amylase and lipase. Jaundice is rare and the liver test abnormalities are most likely due to partial bile duct obstruction. There have been no reports of severe acute hepatitis or acute liver failure attributed to eluxadoline therapy.
Likelihood score: C (probable cause of acute liver injury, likely due to bile duct spasm or obstruction).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the use of eluxadoline during breastfeeding. Because it has opioid agonist activity, an alternate drug is preferred, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
81%

[1]. Pharmaceutics. 2023 May 10;15(5):1460.

Eluxadoline is an amino acid amide obtained by the formal condensation of the carboxy group of 4-carbamoyl-2,6-dimethyl-L-phenylalanine with the secondary amino group of 2-methoxy-5-({[(1S)-1-(4-phenylimidazol-2-yl)ethyl]amino}methyl)benzoic acid. It has mixed opioid receptor activity and is used for treatment of irritable bowel syndrome with diarrhoea. It has a role as a mu-opioid receptor agonist, a delta-opioid receptor antagonist, a kappa-opioid receptor agonist and a gastrointestinal drug. It is a member of imidazoles, a methoxybenzoic acid, a member of benzamides, a L-phenylalanine derivative and an amino acid amide.
Eluxadoline is a DEA Schedule IV controlled substance. Substances in the DEA Schedule IV have a low potential for abuse relative to substances in Schedule III. It is a Other substances substance.
Eluxadoline is a mixed mu-opioid receptor agonist, kappa-opioid receptor agonist, and a-delta opioid receptor antagonist indicated for use in diarrhea-predominant irritable bowel syndrome (IBS-D). The mu-, kappa-, and delta-opioid receptors mediate endogenous and exogenous opioid response in the central nervous system and peripherally in the gastrointestinal system. Agonism of peripheral mu-opioid receptors results in reduced colonic motility, while antagonism of central delta-opioid receptors results in improved analgesia, making eluxadoline usable for the symptoms of both pain and diarrhea characteristic of IBS-D. Marketed under the tradename Viberzi (FDA), eluxadoline is an antimotility agent that decreases bowel contractions, inhibits colonic transit, and reduces fluid/ion secretion resulting in improved symptoms of abdominal pain and reductions in the Bristol Stool Scale.
Eluxadoline is a mu-Opioid Receptor Agonist. The mechanism of action of eluxadoline is as an Opioid mu-Receptor Agonist.
Eluxadoline is a mixed opioid receptor agonist (mu) and antagonist (delta) that is used to treat diarrhea-predominant irritable bowel disease. Eluxadoline is associated with a low rate of serum aminotransferase elevations that appear to be due to isolated instances of sphincter of Oddi spasm and/or pancreatitis that occurs most frequently in persons without a gallbladder.

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Drug Indication
For the treatment of irritable bowel syndrome with diarrhea (IBS-D).
FDA Label
Truberzi is indicated in adults for the treatment of irritable bowel syndrome with diarrhoea (IBS D).
Treatment of diarrhoea-predominant irritable bowel Syndrome

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Mechanism of Action
Eluxadoline is a mu-opioid receptor agonis, kappa opioid receptor agonist and a delta opioid receptor antagonist. Eluxadoline is used for diarrhea predominant IBS because it reduces intestinal contractility and normalizes stress-induced acceleration of upper GI transit. Antagonistic activity at the delta receptor minimizes the constipating effect usually seen by mu-opioid receptor agonists alone. Because of it's limited systemic bioavailability, there may be less side effects associated with the use of eluxadoline in comparison with other therapies used to treat diarrhea predominant IBS.

C32H35N5O5

569.66

569.263

C, 67.47; H, 6.19; N, 12.29; O, 14.04

864821-90-9

864825-13-8 (HCl);864821-90-9;

11250029

Solid powder

1.3±0.1 g/cm3

834.2±65.0 °C at 760 mmHg

458.3±34.3 °C

0.0±3.2 mmHg at 25°C

1.640

4.35

4

7

11

42

917

2

N(C(=O)[C@@H](N)CC1C(C)=CC(C(=O)N)=CC=1C)(CC1C=CC(OC)=C(C(=O)O)C=1)[C@H](C1=NC=C(C2C=CC=CC=2)N1)C

QFNHIDANIVGXPE-FNZWTVRRSA-N

InChI=1S/C32H35N5O5/c1-18-12-23(29(34)38)13-19(2)24(18)15-26(33)31(39)37(17-21-10-11-28(42-4)25(14-21)32(40)41)20(3)30-35-16-27(36-30)22-8-6-5-7-9-22/h5-14,16,20,26H,15,17,33H2,1-4H3,(H2,34,38)(H,35,36)(H,40,41)/t20-,26-/m0/s1

5-(((S)-2-amino-3-(4-carbamoyl-2,6-dimethylphenyl)-N-((S)-1-(5-phenyl-1H-imidazol-2-yl)ethyl)propanamido)methyl)-2-methoxybenzoic acid

JNJ 27018966; JNJ27018966; JNJ-27018966; Trade name: Viberzi

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.)