Ileal bile acid transporter/IBAT (IC50 = 0.53 nM); IL-6; TNF-α/β

Elobixibat reduces BA reabsorption in the terminal ileum, resulting in increased BA excretion in stool and higher BA concentration in the colon, which enhances the secretion of water and electrolytes into the colon, improves intestinal motility, and eases colonic transit.[2]

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Elobixibat (formerly A3309) is a first-in-class ileal bile acid transporter (IBAT) inhibitor for treatment of chronic idiopathic constipation (CIC; syn functional constipation). CIC affects up to 25% of the general population; and up to a half are unsatisfied with current therapies. There is an unmet need for safe and effective drugs to treat CIC.Elobixibat provides a novel approach to treat chronic constipation via IBAT inhibition with enhanced delivery of bile acids to the colon. [1]

Treatment with elobixibat reduced the serum BA and increased the fecal BA concentration, and ameliorated the liver inflammation and fibrosis. It also reduced the expression of proinflammatory cytokines in the liver and MLNs, and transforming growth factor-β expression in the liver. Finally, elobixibat normalized intestinal tight junction protein level and the composition of the intestinal microbiota. Conclusion: elobixibat ameliorates NASH-related histopathology, reduces cytokine expression, and normalizes the intestinal microbial composition in MCD-fed mice, which suggests that it may represent a promising candidate for the therapy of NASH.[3]

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Both groups showed liver fat accumulation and fibrosis, with no significant differences between the two groups. However, mice with elobixibat showed fewer liver tumors. The total serum bile acid levels, including free, tauro-conjugated, glyco-conjugated, and tauro-α/β-muricholic acids in the liver, were noticeably reduced following elobixibattreatment. The proportion of gram-positive bacteria in feces was significantly lower in the group treated with elobixibat (5.4%) than in the group without elobixibat (33.7%). Conclusion: elobixibat suppressed tumor growth by inhibiting bile acid reabsorption, and decreasing total bile acid and primary bile acid levels in the serum and liver. Additionally, the presence of bile acids in the colon may have led to a significant reduction in the proportion of gram-positive bacteria, potentially resulting in decreased secondary bile acid synthesis.[2]

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Pharmacodynamic studies show that it accelerates colonic transit, increases stool frequency, loosens stool consistency and relieves constipation-related symptoms in CIC patients. These beneficial effects are maintained for a minimum of 8 consecutive weeks of treatment. With minimal absorption and low systemic bioavailability, elobixibat is generally well tolerated and may offer the added benefit of improving serum lipid profiles through bile acid depletion.[1]

Three-week-old male C57BL/6J mice were randomly divided into two groups (Fig. 1a): (1) CDHF diet + DEN (control group) and (2) CDHF diet + DEN + elobixibat (elobixibat group) groups. The mice received a single intraperitoneal injection of 25-mg/kg DEN at 3 weeks of age. Then, they were fed a standard diet until they reached 8 weeks of age. For the next 20 weeks, mice in the control group were fed a CDHF diet (60 kcal% fat), while those in the elobixibat group were fed a CDHF diet mixed with elobixibat. The animals were housed in a controlled environment (temperature 23 ± 1 °C, humidity 50 ± 10%, 12-h light/dark cycle) at the animal facility with unlimited access to food and water.[2]

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Dose setting for elobixibat[2]
Elobixibat was calculated to be 0.27 mg/kg/day. This study used animals (mean body weight of 23 g) based on the previously published data. The 50% inhibitory concentration of human IBAT is 0.53 nmol/L, and that of mouse IBAT is 0.13 nmol/L. Therefore, the inhibitory activity is four times higher in mice than in humans. The concentration of elobixibat in mice at 70% effective dose is 2.7 mg/kg; while at 50% effective dose, it is 0.27 (70% × [0.023/60])0.33 = 2.23 mg/kg; this would be 110 mg/day for a 50-kg human, 11 times the amount normally used. Therefore, we set our effective capacity at 50%: 0.27 (50%) × [0.023/60])0.33 = 0.223 mg/kg. A CDHF + elobixibat diet containing 3 mg elobixibat per kg of CDHF diet was created and used based on the mean expected body weight and expected food intake.[2]

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Elobixibat (1.2 mg/kg/day) was administered for the final 4 weeks of this period (elobixibat group). At the end of the study period, the mice were euthanized by inhalation of carbon dioxide.[2]
Doses of 0.2, 0.6, or 1.2 mg/kg of elobixibat were administered for 4 weeks, 5 days per week, by oral gavage. Both the control group and the MCD-NASH group were administered PBS on the same schedule by oral gavage. There were no clear effects of 0.2 mg/kg or 0.6 mg/kg (data not shown), but beneficial effects were observed at the 1.2 mg/kg/day dose. This concentration is 4–6 times the dosage for human. According to “Drug Interview Form of Elobixibat”, elobixibat showed strong inhibitory activity to human IBAT, which was about four times more than that of mouse IBAT. Therefore, a dose of 1.2 mg/kg/day in mice is considered equivalent to 0.3 mg/kg/day in human. We evaluated the effects of this dose on the severity of NASH, cytokine production, the intestinal microbiota, and the intestinal TJs in the mice. No diarrhea was observed during the rearing period, and there was no difference in body weight between the NASH and elobixibat groups at the end of the experiment.[2]

[1]. Elobixibat for the treatment of constipation. Expert Opin Investig Drugs. 2013 Feb; 22(2):277-84.
[2].Impact of elobixibat on liver tumors, microbiome, and bile acid levels in a mouse model of nonalcoholic steatohepatitis. Hepatol Int. 2023 Dec;17(6):1378-1392.
[3].Elobixibat, an ileal bile acid transporter inhibitor, ameliorates non-alcoholic steatohepatitis in mice. Hepatol Int. 2021 Apr;15(2):392-404.

Elobixibat has been used in trials studying the treatment and basic science of Dyslipidemia, Constipation, Chronic Constipation, Functional Constipation, and Chronic Idiopathic Constipation.

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Drug Indication
Treatment of chronic constipation

C36H45N3O7S2

695.8884

695.27

C, 62.14; H, 6.52; N, 6.04; O, 16.09; S, 9.21

439087-18-0

Elobixibat hydrate;1633824-78-8; 439087-68-0 (S-isomer)

9939892

Typically exists as White to off-white solid at room temperature

8.964

3

9

16

48

1140

1

S1(C2=C([H])C(=C(C([H])=C2N(C2C([H])=C([H])C([H])=C([H])C=2[H])C([H])([H])C(C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H])(C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H])C1([H])[H])SC([H])([H])[H])OC([H])([H])C(N([H])[C@@]([H])(C(N([H])C([H])([H])C(=O)O[H])=O)C1C([H])=C([H])C([H])=C([H])C=1[H])=O)(=O)=O

XFLQIRAKKLNXRQ-UUWRZZSWSA-N

InChI=1S/C36H45N3O7S2/c1-4-6-18-36(19-7-5-2)24-39(27-16-12-9-13-17-27)28-20-30(47-3)29(21-31(28)48(44,45)25-36)46-23-32(40)38-34(26-14-10-8-11-15-26)35(43)37-22-33(41)42/h8-17,20-21,34H,4-7,18-19,22-25H2,1-3H3,(H,37,43)(H,38,40)(H,41,42)/t34-/m1/s1

(R)-(2-(2-((3,3-dibutyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-8-yl)oxy)acetamido)-2-phenylacetyl)glycine

AZD-7806; AZD 7806; AZD7806; A 3309; 439087-18-0; AZD7806; AZD-7806; A3309; 865UEK4EJC; A-3309; 2-[[(2R)-2-[[2-[(3,3-dibutyl-7-methylsulfanyl-1,1-dioxo-5-phenyl-2,4-dihydro-1lambda6,5-benzothiazepin-8-yl)oxy]acetyl]amino]-2-phenylacetyl]amino]acetic acid; A3309; A-3309; AJG-533

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)

DMSO : ~250 mg/mL (~359.25 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (2.99 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: 2.08 mg/mL (2.99 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
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.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (2.99 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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