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 )

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].

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.

Absorption, Distribution and Excretion
Alvimopan's high affinity for the peripheral mu-receptor leads to slower absorption dependent on dissociation from the receptor and subsequently low oral bioavailability of less than 7%.
Biliary secretion was considered the primary pathway for alvimopan elimination. Unabsorbed drug and unchanged alvimopan resulting from biliary excretion were then hydrolyzed to its ‘metabolite’ by gut microflora. Feces (via biliary excretion) & urine (35%)
30±10 L
402 ± 89 mL/min
Following oral administration of Entereg capsules in healthy volunteers, plasma alvimopan concentration peaked at approximately 2 hours postdose. No significant accumulation in alvimopan concentration was observed following twice daily (BID) dosing. The mean peak plasma concentration was 10.98 (+ or - 6.43) ng/mL and mean AUC0-12hr was 40.2 (+ or - 22.5) ng hr/mL after dosing of alvimopan at 12 mg BID for 5 days. The absolute bioavailability was estimated to be 6% (range, 1% to 19%). Plasma concentrations of alvimopan increased approximately proportionally with increasing doses between 6 and 18 mg, but less than proportionally from 18 to 24 mg.
Alvimopan and its metabolite are distributed into milk in rats; it is unknown whether the drug or its metabolite is distributed into human milk.
The steady state volume of distribution of alvimopan was estimated to be 30 + or - 10 L. Plasma protein binding of alvimopan and its metabolite was independent of concentration over ranges observed clinically and averaged 80% and 94%, respectively. Both alvimopan and the metabolite were bound to albumin and not to alpha-1 acid glycoprotein.
The average plasma clearance for alvimopan was 402 (+ or - 89) mL/min. Renal excretion accounted for approximately 35% of total clearance. There was no evidence that hepatic metabolism was a significant route for alvimopan elimination. Biliary secretion was considered the primary pathway for alvimopan elimination. Unabsorbed drug and unchanged alvimopan resulting from biliary excretion were then hydrolyzed to its metabolite by gut microflora. The metabolite was eliminated in the feces and in the urine as unchanged metabolite, the glucuronide conjugate of the metabolite, and other minor metabolites.
... The population pharmacokinetics of orally administered alvimopan and its primary metabolite in healthy subjects/special populations, and surgical patients at risk for ileus /was characterized/. Models were consistent with known physiology/pharmacology. Alvimopan's model had two compartments with first-order elimination. Metabolite was modeled with a catenary chain and lag for alvimopan's metabolism within the gut followed by absorption, one systemic compartment with first-order elimination. Weight, gender, and renal function did not affect alvimopan or metabolite. Steady-state alvimopan and metabolite concentrations were 87 and 40% higher, respectively, in patients. Alvimopan concentrations were 35% higher in the elderly, but were not affected by race, acid blockers, or antibiotics. Metabolite concentrations were 43 and 82% lower in African Americans and Hispanics, respectively, compared to Caucasians, 49% lower with acid blockers and 81% lower with preoperative antibiotics. Although alvimopan's pharmacokinetics was described with a traditional model, its metabolite required a novel model accommodating gut metabolism.

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Metabolism / Metabolites
Alvimopan is primarily metabolized by intestinal flora to an active metabolite although it has no clinically significant contribution to the effects of the drug.
... There was no evidence that hepatic metabolism was a significant route for alvimopan elimination. ... Unabsorbed drug and unchanged alvimopan resulting from biliary excretion were then hydrolyzed to its metabolite by gut microflora. The metabolite was eliminated in the feces and in the urine as unchanged metabolite, the glucuronide conjugate of the metabolite, and other minor metabolites.
Following oral administration of alvimopan, an amide hydrolysis compound is present in the systemic circulation, which is considered a product exclusively of intestinal flora metabolism. This compound is referred to as the metabolite. It is also a mu-opioid receptor antagonist with a Ki of 0.8 nM (0.3 ng/mL). ... There was a delay in the appearance of the metabolite, which had a median Tmax of 36 hours following administration of a single dose of alvimopan. Concentrations of the metabolite were highly variable between subjects and within a subject. The metabolite accumulated after multiple doses of ENTEREG. The mean Cmax for the metabolite after alvimopan 12 mg twice daily for 5 days was 35.73 + or - 35.29 ng/mL.

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Biological Half-Life
10 to 17 hours (gut metabolite: 10 to 18 hours)
The mean terminal phase half-life of alvimopan after multiple oral doses of Entereg ranged from 10 to 17 hours. The terminal half-life of the metabolite ranged 10 to 18 hours.

Protein Binding
80% to 90% bound in after entering systemic circulation.

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

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

Therapeutic Uses
Gastrointestinal Agents
Entereg is indicated to accelerate the time to upper and lower gastrointestinal recovery following partial large or small bowel resection surgery with primary anastomosis. /Included in US product label/
Although alvimopan has been studied for the management of postoperative ileus in women undergoing total abdominal hysterectomy under general anesthesia, efficacy of the drug for this indication has not been established to date. /NOT included in US product label/
/EXPL/ Our objective was to investigate the efficacy and safety of alvimopan, a peripherally acting mu-opioid receptor (PAM-OR) antagonist, in subjects with non-cancer pain and opioid-induced bowel dysfunction (OBD), and to identify at least one treatment regimen that improves OBD. Following a 2-week baseline period, 522 subjects reporting <3 spontaneous bowel movements (SBMs)/week (with >or= 25% accompanied by a sensation of incomplete evacuation, straining, or lumpy hard stools), requiring analgesia equivalent to >or= 30 mg oral morphine/day were randomized to alvimopan 0.5 mg twice daily (BID), 1mg once daily (QD), 1 mg BID, or placebo for 6 weeks. Compared with placebo, there was a statistically and clinically significant increase in mean weekly SBM frequency over the initial 3 weeks of treatment (primary endpoint) with alvimopan 0.5 mg BID (+1.71 mean SBMs/week), alvimopan 1mg QD (+1.64) and alvimopan 1 mg BID (+2.52); P<0.001 for all comparisons. Increased SBM frequency and additional treatment effects, including improvements in symptoms such as straining, stool consistency, incomplete evacuation, abdominal bloating/discomfort, and decreased appetite, were sustained over 6 weeks. The most frequently reported adverse events were abdominal pain, nausea, and diarrhea, occurring more frequently in the higher dosage groups. The alvimopan 0.5 mg BID regimen demonstrated the best benefit-to-risk profile for managing OBD with alvimopan in this study population, with a side effect profile similar to that of placebo. There was no evidence of opioid analgesia antagonism. Competitive peripheral antagonism of opioids with alvimopan can restore GI function and relieve OBD without compromising analgesia.

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Drug Warnings
/BOXED WARNING/ WARNING: POTENTIAL RISK OF MYOCARDIAL INFARCTION WITH LONG-TERM USE: FOR SHORT-TERM HOSPITAL USE ONLY. There was a greater incidence of myocardial infarction in alvimopan-treated patients compared to placebo-treated patients in a 12-month clinical trial, although a causal relationship has not been established. In short-term trials with Entereg, no increased risk of myocardial infarction was observed. Because of the potential risk of myocardial infarction with long-term use, Entereg is available only through a restricted program for short-term use (15 doses) under a Risk Evaluation and Mitigation Strategy (REMS) called the Entereg Access Support and Education (E.A.S.E.) Program [see
A numerically higher incidence of myocardial infarction was reported in patients receiving alvimopan 0.5 mg twice daily compared with placebo in a 12-month clinical study evaluating long-term use of the drug for management of opiate-induced bowel dysfunction in patients with chronic pain; a majority of events occurred 1 - 4 months after initiation of therapy. Similar results have not been observed in patients receiving short-term alvimopan therapy (12 mg twice daily for 7 days or less) following bowel resection. A causal relationship between myocardial infarction and alvimopan has not been established. Because of an increased risk of ischemic cardiac events with long-term therapy, alvimopan is available only to hospitals through a restricted distribution program (EASE program).
Use of alvimopan in patients undergoing surgical correction of complete bowel obstruction is not recommended.
Increased variability in alvimopan pharmacokinetics has been observed in patients with active or quiescent Crohn's disease; exposure to the drug generally was twofold higher in patients with quiescent disease compared with healthy individuals or patients with active disease. Concentrations of alvimopan's metabolite were lower in patients with Crohn's disease. However, the manufacturer states that dosage adjustments are not necessary.
For more Drug Warnings (Complete) data for ALVIMOPAN (12 total), please visit the HSDB record page.

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.

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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.)