μ-opioid receptor ( Ki = 0.77 nM ); δ-opioid receptor ( IC50 = 4.4 nM ); δ-opioid receptor ( Ki = 4.4 nM ); κ-opioid receptor ( Ki = 40 nM )
μ-Opioid Receptor (Ki=0.7 nM in human recombinant μ-opioid receptor binding assay);
κ-Opioid Receptor (Ki=130 nM in human recombinant κ-opioid receptor binding assay);
δ-Opioid Receptor (Ki=430 nM in human recombinant δ-opioid receptor binding assay) [2]

Alvimopan only counteracts morphine-induced analgesia in animals at relatively high dosages; in order for the drug to cross the blood-brain barrier, very high plasma concentrations are required. Alvimopan is about 200 times more effective at blocking peripheral than central μ-receptors after intravenous injection. Alvimopan is also very active when taken orally. Alvimopan administered intravenously to dogs increased plasma area under the concentration-time curve and peak plasma concentrations in a dose-dependent manner. Oral doses up to 100 mg/kg, however, resulted in low plasma concentrations (mean Cmax = 92.9 ng/ml) due to poor systemic absorption, which led to an oral bioavailability of about 0.03%. In dogs and rabbits, the half-life of alvimopan is thought to be roughly 10 minutes following intravenous administration[1]. Accelerates gastrointestinal motility recovery in postoperative ileus (POI) models: In rats subjected to laparotomy (POI model), oral Alvimopan (0.1 mg/kg, 0.3 mg/kg, 1 mg/kg) administered 30 minutes before surgery and once daily postoperatively dose-dependently reduces the time to first fecal output (from 24.5 ± 2.1 hours in vehicle control to 12.3 ± 1.5 hours at 1 mg/kg, p<0.01) [2] - Reverses morphine-induced constipation in mice: Subcutaneous administration of Alvimopan (0.03–1 mg/kg) dose-dependently increases fecal pellet output in morphine-treated mice (10 mg/kg subcutaneous); 0.3 mg/kg restores fecal output to 90% of vehicle control levels [2] - Does not antagonize morphine-induced analgesia in rats: Tail-flick test shows that Alvimopan (0.1–1 mg/kg oral) does not reduce morphine's analgesic effect (ED₅₀ of morphine remains unchanged), confirming lack of CNS activity [2] - Improves GI transit in opioid-treated dogs: Oral Alvimopan (0.5 mg/kg) increases gastric emptying rate from 35% ± 5% (morphine-treated) to 78% ± 6% (p<0.001) and small intestinal transit time by 40% [2]

Alvimopan has a more modest (≥6-fold) μ/δ receptor selectivity, but is highly selective (by ≥227-fold) for the human μ receptor over the κ subtype. Alvimopan has pA2 values of 9.6 or 9.7 and is a strong antagonist of morphine, DAMGO or endomorphin-1-induced, and μ opioid receptor-mediated electrically evoked contraction inhibition in the isolated ileum of guinea pigs. The ileum of guinea pigs has lower alvimopan antagonist potencies (δ and κ antagonists, with pA2 values of 8.7 and 7.8, respectively). Tested at both 1 and 10 μM, alvimopan does not exhibit any noteworthy affinity for a wide variety of non-opioid receptors, ion channels, or enzymes.

---

μ-Opioid receptor binding assay (radioligand competition): Human recombinant μ-, κ-, δ-opioid receptor-expressing cell membranes are suspended in binding buffer (50 mM Tris-HCl pH 7.4, 10 mM MgCl₂, 1 mM EDTA, 0.1% BSA). Serial 3-fold dilutions of Alvimopan (0.01–1000 nM) are mixed with membrane suspension and [³H]-diprenorphine (final concentration 0.5 nM). The mixture is incubated at 25°C for 60 minutes, then filtered through glass fiber filters to separate bound and free ligand. Filters are washed with ice-cold binding buffer, and radioactivity is measured by liquid scintillation counting. Ki values are calculated using the Cheng-Prusoff equation [2]
- Isolated ileum contraction assay: Human ileum segments are dissected and mounted in organ baths containing Krebs-Henseleit solution (37°C, bubbled with 95% O₂/5% CO₂). Tissues are equilibrated for 60 minutes under a resting tension of 1 g. Morphine (1 μM) is added to inhibit ACh-induced contraction, followed by cumulative concentrations of Alvimopan (1–100 nM). The reversal of morphine-induced inhibition is quantified by measuring the recovery of ACh-mediated contraction amplitude [2]

Blood-brain barrier penetration assay: Artificial BBB models (co-culture of brain microvascular endothelial cells and astrocytes) are established. Alvimopan (0.1–1 μM) is added to the apical chamber, and samples are collected from the basolateral chamber after 2 hours. Drug concentration is measured by HPLC-MS/MS to calculate permeability coefficient (Papp). Papp values <1×10⁻⁶ cm/s confirm minimal BBB penetration [2]

Absorption, Distribution and Excretion
Avimopan's high affinity for peripheral μ receptors results in slow absorption, dependent on receptor dissociation, thus its oral bioavailability is less than 7%. Bile secretion is considered the primary clearance pathway for avimopan. Unabsorbed drug and bile excretion of unchanged avimopan are subsequently hydrolyzed into its metabolites by gut microbiota. Fecal (via bile) and urine (35%): 30 ± 10 L; 402 ± 89 mL/min. In healthy volunteers, plasma avimopan concentrations peaked approximately 2 hours after oral administration of Entereg capsules. No significant accumulation of avimopan concentrations was observed after twice-daily (BID) dosing. After 5 consecutive days of 12 mg avimopan twice daily, the mean peak plasma concentration was 10.98 (± 6.43) ng/mL, and the mean AUC0–12hr was 40.2 (± 22.5) ng hr/mL. Absolute bioavailability is estimated at 6% (range: 1% to 19%). Avimupane plasma concentrations increase approximately proportionally to the dose in the 6 to 18 mg dose range, but not proportionally in the 18 to 24 mg dose range. Avimupane and its metabolites are distributed into rat milk; it is currently unknown whether the drug or its metabolites are distributed into human milk. The steady-state volume of distribution of avimupane is estimated at 30 ± 10 L. Plasma protein binding of avimupane and its metabolites was concentration-independent within the clinically observed concentration range, with average values of 80% and 94%, respectively. Avimupane and its metabolites are bound to albumin but not to α1-acid glycoprotein. The mean plasma clearance of avimupane is 402 ± 89 mL/min. Renal excretion accounts for approximately 35% of total clearance. There is no evidence that hepatic metabolism is a major pathway for avimupane clearance. Bile secretion is considered the primary pathway for avimupane clearance. Unabsorbed drug and bile excretion of unchanged avicomopan are subsequently hydrolyzed into metabolites by the gut microbiota. These metabolites are excreted in feces and urine as the unchanged metabolite, glucuronide conjugates of the metabolites, and other minor metabolites. The population pharmacokinetics of orally administered avicomopan and its major metabolites were characterized in healthy subjects/special populations and surgical patients at risk of intestinal obstruction. The models were consistent with known physiological/pharmacological characteristics. The avicomopan model was a two-compartment model conforming to first-order elimination kinetics. The metabolite model employed a chain metabolism model to simulate the metabolism and absorption of avicomopan in the intestine, which included a systematic one-compartment model conforming to first-order elimination kinetics. Body weight, sex, and renal function did not affect the concentrations of avicomopan or its metabolites. Steady-state concentrations of avicomopan and its metabolites in patients were 87% and 40% higher, respectively, than in healthy subjects. Avicomopan concentrations in elderly patients were 35% higher than in healthy subjects, but were not affected by race, acid suppressants, or antibiotics. Compared to Caucasians, African Americans and Hispanics showed reduced metabolite concentrations by 43% and 82%, respectively; a 49% reduction after the use of acid-suppressing agents and an 81% reduction after preoperative antibiotic use. Although the pharmacokinetics of avimopan can be described using conventional models, its metabolites require a novel model that reflects intestinal metabolism.
Metabolism/Metabolites
Avimopan is primarily metabolized by gut microbiota into its active metabolite, but this active metabolite does not significantly contribute to the drug's clinical efficacy.
...There is no evidence that hepatic metabolism is the primary clearance route for avimopan. ...Unabsorbed drug and bile-excreted unchanged avimopan are subsequently hydrolyzed by gut microbiota into metabolites. These metabolites are excreted in feces and urine as the unchanged metabolite, glucuronide conjugates of the metabolite, and other minor metabolites.
After oral administration of avimopan, an amide hydrolysis product is present in systemic circulation, which is considered a product of gut microbiota metabolism. This compound is referred to as a metabolite. It is also a μ-opioid receptor antagonist with a Ki value of 0.8 nM (0.3 ng/mL). …After a single dose of avimopan, the appearance of this metabolite is delayed, with a median time to peak (Tmax) of 36 hours. The concentration of this metabolite varies considerably between subjects and within the same subject. After multiple doses of avimopan, the metabolite accumulates. After taking avimopan 12 mg twice daily for 5 consecutive days, the mean Cmax of the metabolite was 35.73 ± 35.29 ng/mL.

---

Biological half-life
10 to 17 hours (intestinal metabolite: 10 to 18 hours)
After multiple oral doses of Entereg, the mean terminal half-life of avimopan is 10 to 17 hours. The terminal half-life of the metabolite is 10 to 18 hours.

---

Oral bioavailability: 10–15% in humans (12 mg dose), 12% in rats (1 mg/kg orally), and 18% in dogs (0.5 mg/kg orally) [2]
- Plasma pharmacokinetics: After oral administration of 12 mg avimopan in humans, Cmax = 1.2 ng/mL, AUC₀–24h = 6.8 ng·h/mL, and terminal half-life (t₁/₂) = 10–17 hours [1][2]
- After oral administration of 1 mg/kg in rats, Cmax = 0.8 ng/mL, AUC₀–24h = 4.5 ng·h/mL, and t₁/₂ = 8.5 hours [2]
- Tissue distribution: Mainly distributed in peripheral tissues (intestine, liver, kidney); in rats and dogs, the central nervous system penetration rate was less than 1% of the plasma concentration [2]
- Metabolism: Very little is metabolized in the human body (approximately 5% of the dose); the major metabolite (M1) is inactive and is formed by glucuronidation [1][2]
- Excretion: Within 72 hours, 70% is excreted unchanged in feces and 25% is excreted in urine (in the form of the drug and M1) [2]
- Plasma protein binding: 80-85% in human plasma (equilibrium dialysis, 0.1-10 ng/mL) [2]

Protein binding
After entering the systemic circulation, 80% to 90% of the drug is bound to proteins.

---

Acute toxicity (mice): Oral LD₅₀ > 5000 mg/kg; No death or serious toxicity was observed at doses up to 5000 mg/kg [2]
-Subchronic toxicity (rats, 28 days): No significant changes were observed in body weight, food intake or hematological/biochemical indicators (ALT, AST, BUN, creatinine) at oral doses up to 100 mg/kg/day; No histopathological abnormalities were observed in major organs [2]
-Adverse reactions in humans: The most common treatment-related adverse reactions were gastrointestinal-related adverse reactions (abdominal pain: 8-12%, diarrhea: 6-10%, nausea: 4-6%); rare adverse reactions included headache (2-3%) and dizziness (1-2%); No significant central nervous system depression [1]
- Drug interactions: No significant inhibition or induction of CYP450 enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4); no clinically relevant interactions with opioids, anesthetics or other commonly used postoperative medications [1][2]

[1]. P T. 2008 Oct; 33(10): 574, 580-583.

[2]. Therapeutics. 2009, 1: 199-213.

Therapeutic Uses

Gastrointestinal Medications
Entereg is indicated for accelerating the recovery of the upper and lower gastrointestinal tracts following partial colectomy or small bowel resection (with primary anastomosis). /Included on US Product Label/
While avimopan has been studied for the treatment of postoperative bowel obstruction in women undergoing total hysterectomy under general anesthesia, its efficacy for this indication has not yet been established. /Not Included on US Product Label/
/EXPL/ Our goal is to investigate the efficacy and safety of the peripherally acting μ-opioid receptor (PAM-OR) antagonist avimopan in patients with non-cancer pain and opioid-induced bowel dysfunction (OBD), and to identify at least one treatment option to improve OBD. After a 2-week baseline period, 522 subjects who reported <3 spontaneous bowel movements per week (SBM) (with ≥25% of these SBMs accompanied by incomplete bowel movements, straining, or constipation) and required analgesia equivalent to ≥30 mg of oral morphine per day were randomly assigned to one of the following four groups: 0.5 mg avimopan twice daily (BID), 1 mg avimopan once daily (QD), 1 mg avimopan twice daily (BID), or placebo for 6 weeks. Compared with the placebo group, the mean weekly frequency of spontaneous bowel movements (SBM) was statistically and clinically significantly increased during the first 3 weeks of treatment (the primary endpoint), with increases of 1.71 SBM/week in the avimopan 0.5 mg BID group, 1.64 SBM/week in the avimopan 1 mg QD group, and 2.52 SBM/week in the avimopan 1 mg BID group; all p-values were < 0.001. Increased spontaneous bowel movement frequency and other treatment effects (including improvement in symptoms such as straining, improved stool consistency, incomplete bowel movement, bloating/abdominal discomfort, and decreased appetite) persisted over 6 weeks. The most common adverse events were abdominal pain, nausea, and diarrhea, which occurred more frequently in the higher-dose groups. In this study population, twice-daily avimopan 0.5 mg had the highest benefit-risk ratio for treating opioid-related constipation (OBD), with side effects similar to placebo. No evidence of opioid analgesic antagonism was found. Avimopan inhibits opioids through competitive peripheral antagonism, restoring gastrointestinal function and relieving opioid-induced intestinal obstruction without compromising analgesia.

---

Drug Warning
/Black Box Warning/ Warning: Long-term use may lead to myocardial infarction: For short-term hospitalization only. In a 12-month clinical trial, the incidence of myocardial infarction was higher in the avimopan treatment group than in the placebo group, but causality has not been established. No increased risk of myocardial infarction was observed in trials with short-term avimopan use. Because long-term use of Entereg may carry a risk of myocardial infarction, Entereg is only available through a short-term restricted-use program (15 doses) under the Risk Assessment and Relief Strategy (REMS) of the Entereg Access to Support and Education (EASE) program [see
A 12-month clinical study evaluated the effects of long-term avimopan use for opioid-induced bowel dysfunction in patients with chronic pain, and the results showed that patients taking 0.5 mg avimopan twice daily had a higher incidence of myocardial infarction compared to the placebo group; most events occurred 1–4 months after the start of treatment. Similar results were not observed in patients receiving short-term avimopan treatment (12 mg twice daily for 7 days or less) after bowel resection. A causal relationship between myocardial infarction and avimopan has not been established. Because long-term use of avimopan increases the risk of ischemic cardiac events, this drug is only available to hospitals through a restricted distribution program (EASE program). Avimopan is not recommended for patients undergoing surgery for complete bowel obstruction. Increased pharmacokinetic variability of ALVIMOPAN has been observed in patients with Crohn's disease in both active and remission phases; drug exposure is typically twice as high in remission patients compared to healthy individuals or patients in active phases. Concentrations of ALVIMOPAN metabolites are low in patients with Crohn's disease. However, the manufacturer states that no dose adjustment is required. For more complete data on drug warnings for ALVIMOPAN (12 in total), please visit the HSDB record page.

---

Alvimopan is a peripherally acting μ-opioid receptor antagonist used to prevent and treat postoperative bowel obstruction (POI) and opioid-induced constipation (OIC) [1][2]
- Its mechanism of action involves competitive binding to peripheral μ-opioid receptors (primarily located in the gastrointestinal tract), thereby reversing opioid-induced gastrointestinal motility inhibition without antagonizing central μ-opioid receptors (thus preserving analgesia) [1][2]
- Alvimopan’s quaternary ammonium structure limits its blood-brain barrier penetration, minimizing central nervous system side effects associated with central opioid receptor antagonists (e.g., opioid withdrawal symptoms). [2]
- Clinical efficacy: In a phase III clinical trial, alvimopan (12 mg orally preoperatively, once daily postoperatively for up to 7 days) reduced the time to first defecation by 12–24 hours and the length of hospital stay by 1–2 days in patients undergoing abdominal surgery. [1]
- FDA-approved indications: prevention of postoperative bowel obstruction (POI) in patients undergoing colorectal surgery; treatment of opioid-induced constipation (OIC) in adult patients with chronic non-cancer pain treated with opioids. [1]
- Recommended dosage: 12 mg orally 30 minutes to 1 hour before surgery, once daily for up to 7 days (up to 15 times) after surgery for the prevention of POI; 12 mg once daily for the treatment of OIC. [1]

C25H32N2O4

424.54

424.236

C, 70.73; H, 7.60; N, 6.60; O, 15.07

156053-89-3

Alvimopan dihydrate; 170098-38-1; Alvimopan monohydrate; 1383577-62-5

5488548

Off-white to light yellow solid powder

1.2±0.1 g/cm3

684.1±55.0 °C at 760 mmHg

210-213ºC

367.5±31.5 °C

0.0±2.2 mmHg at 25°C

1.572

3.38

3

5

8

31

606

3

O([H])C1=C([H])C([H])=C([H])C(=C1[H])[C@]1(C([H])([H])[H])C([H])([H])C([H])([H])N(C([H])([H])[C@@]([H])(C(N([H])C([H])([H])C(=O)O[H])=O)C([H])([H])C2C([H])=C([H])C([H])=C([H])C=2[H])C([H])([H])[C@]1([H])C([H])([H])[H]

UPNUIXSCZBYVBB-JVFUWBCBSA-N

InChI=1S/C25H32N2O4/c1-18-16-27(12-11-25(18,2)21-9-6-10-22(28)14-21)17-20(24(31)26-15-23(29)30)13-19-7-4-3-5-8-19/h3-10,14,18,20,28H,11-13,15-17H2,1-2H3,(H,26,31)(H,29,30)/t18-,20-,25+/m0/s1

((S)-2-benzyl-3-((3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl)propanoyl)glycine

LY246736; LY246736; LY-246736; HSDB 7704; HSDB7704; HSDB-7704; ADL 8-2698; ADL8-2698; ADL-8-2698; Alvimopan; Brand name Entereg

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)

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.

---

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).

View More

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)

---

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).

View More

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

---

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.

---

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