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]

---

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]

Elobixbat(原A3309)可减少BA在回肠末端的重吸收，导致粪便中BA排泄量增加，结肠中BA浓度升高，从而促进水和电解质向结肠的分泌，改善肠道动力，缓解结肠运输[2]。

---

Elobixbat(原A3309)是一种一流的回肠胆汁酸转运蛋白(IBAT)抑制剂，用于治疗慢性特发性便秘(CIC;Syn功能性便秘)。多达25%的人口受CIC影响;多达一半的人对目前的治疗方法不满意。目前对安全有效的CIC治疗药物的需求还没有得到满足。依洛比昔巴提供了一种新的方法，通过IBAT抑制，增强胆汁酸向结肠的输送，治疗慢性便秘。[1]

---

在使用过表达哺乳动物胆汁酸转运蛋白的HEK-293细胞进行的竞争性抑制实验中，Elobixibat 能以浓度依赖的方式抑制30 µM放射性标记的甘氨胆酸通过回肠胆汁酸转运蛋白（IBAT）的细胞内积聚。这证实了其对IBAT的强效和选择性抑制。[1]

Elobixibat治疗可降低血清BA，增加粪便BA浓度，改善肝脏炎症和纤维化。它还降低了肝脏和mln中促炎因子的表达以及肝脏中转化生长因子-β的表达。最后，elobixibat使肠道紧密连接蛋白水平和肠道微生物群组成正常化。 结论:elobixibat改善mcd喂养小鼠NASH相关组织病理学，降低细胞因子表达，并使肠道微生物组成正常化，这表明它可能是治疗NASH的有希望的候选药物。[3]

---

两组均出现肝脏脂肪堆积和纤维化，两组间差异无统计学意义。然而，使用elobixibat的小鼠肝脏肿瘤较少。血清总胆汁酸水平，包括游离胆汁酸、牛磺酸偶联胆汁酸、糖偶联胆汁酸和牛磺酸-α/β-胆酸，在elobixibat治疗后显著降低。伊洛比西巴治疗组粪便中革兰氏阳性菌比例(5.4%)显著低于未治疗组(33.7%)。 结论:elobixibat通过抑制胆汁酸重吸收，降低血清和肝脏中总胆汁酸和原胆汁酸水平来抑制肿瘤生长。此外，胆汁酸在结肠中的存在可能导致革兰氏阳性菌的比例显著减少，可能导致继发性胆汁酸合成减少[2]。

---

药效学研究表明，它能加速CIC患者的结肠运输，增加大便频率，使大便粘稠度变松，缓解便秘相关症状。这些有益效果至少可以连续治疗8周。elobixibat具有最小的吸收和较低的全身生物利用度，通常耐受性良好，并且可能通过胆汁酸消耗提供改善血清脂质谱的额外益处。[1]

---

在健康比格犬的肉类诱导便秘临床前模型中，口服Elobixibat（剂量为1.5、5和15 µmol/kg/天）可增加粪便重量。5和15 µmol/kg/天的剂量使粪便重量增加近3.5倍，与溶剂对照组相比具有统计学显著性。[1]
在犬类中，连续28天口服Elobixibat（剂量为5、25和200 µmol/kg/天）可剂量依赖性增加肝脏胆汁酸合成，该效应通过血浆中胆汁酸合成中间体7α-羟基-4-胆甾烯-3-酮（C4）的水平来测量。C4水平的升高在给药后24小时即可检测到，并在28天内持续维持。[1]
在一项涉及30名CIC患者的I期人体研究中，连续14天每日服用3 mg和10 mg的Elobixibat 与安慰剂相比，显著加速了结肠传输时间（CTT），主要加速部位在左半结肠。血浆C4水平升高，总胆固醇和低密度脂蛋白胆固醇剂量依赖性降低。观察到自发排便次数增加和粪便变软的趋势，特别是在10 mg剂量组。[1]
在一项涉及36名女性功能性便秘患者的IIa期人体研究中，连续14天每日服用15 mg和20 mg的Elobixibat 显著加速了结肠传输（20 mg剂量在8、24和48小时均加速；15 mg剂量在48小时加速）。粪便稠度显著变软，排便费力程度减轻，排便通畅感改善。血清C4水平剂量依赖性升高（15 mg组约2倍，20 mg组约3倍）。[1]
在一项涉及190名CIC患者的IIb期人体试验中，连续8周每日服用10 mg和15 mg的Elobixibat 与安慰剂相比，显著增加了每周自发排便次数相对于基线的变化。增加效果是剂量依赖性的，并在8周治疗期内持续存在。首次自发排便的时间显著缩短。粪便变软，排便费力减轻，腹胀严重程度改善（15 mg组）。血浆C4水平升高，总胆固醇和低密度脂蛋白胆固醇在10 mg和15 mg剂量组均下降。[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]

---

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]

---

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]

---

In a preclinical constipation model, healthy beagle dogs were fed a beef diet for up to 14 days to induce constipation (defined as wet stool weight < 30 g/day). Elobixibat was administered orally at doses of 1.5, 5, and 15 µmol/kg/day. Stool weight was measured as the primary outcome to assess laxative effect. [1]
In a separate 28-day pharmacodynamic study in dogs, Elobixibat was administered orally at doses of 5, 25, and 200 µmol/kg/day consecutively. Blood samples were taken to measure plasma levels of 7α-hydroxy-4-cholesten-3-one (C4), a biomarker for hepatic bile acid synthesis, at various time points including 24 hours and after 28 days of treatment. [1]

In a Phase I trial in humans, plasma concentrations of Elobixibat were very low following oral administration. The drug was undetectable at doses of 0.1 and 0.3 mg/day, and only detectable in the picomolar range at doses between 1 and 10 mg/day. The highest plasma concentration observed was 0.76 nmol/L. [1]
The time to maximum plasma concentration (Tₘₐₓ) occurred within 4 hours of dosing. [1]
Plasma elimination occurred within 24 hours of dosing. [1]
Elobixibat is minimally absorbed from the gastrointestinal tract after oral administration, resulting in very low systemic bioavailability. [1]
The parent compound and no metabolites were detectable in plasma. [1]
Elobixibat is highly protein-bound in plasma (>99%). [1]
The plasma half-life (t½) is less than 4 hours. [1]
Elobixibat inhibits cytochrome P450 enzymes CYP2C9 and CYP3A4 in vitro with IC₅₀ values of 10.3 µM and 6.0 µM, respectively. However, due to its minimal systemic absorption, the risk of clinically relevant drug-drug interactions via this mechanism after oral dosing is considered low. [1]

In Phase I and II clinical trials, no serious adverse events related to Elobixibat were reported. [1]
The most common adverse events were gastrointestinal in nature. In a Phase IIa study, mild to moderate abdominal cramps or pain occurred more frequently in the 15 mg (4 of 12 patients) and 20 mg (6 of 12 patients) groups compared to placebo (0 of 13). This pain often preceded bowel movements and resolved afterwards. [1]
Diarrhea occurred more frequently at higher doses (four patients in the 20 mg group vs. one each in the 15 mg and placebo groups in the Phase IIa study). All study withdrawals due to adverse events were related to diarrhea. [1]
In an 8-week Phase IIb study, the treatment discontinuation rate was higher in the 15 mg group (23%) compared to placebo and lower dose groups (~13%). Adverse events were reported in 54% of patients overall, with 7% being severe. Serious adverse events occurred in three patients but were deemed unrelated to the study medication. [1]
There is a theoretical concern that increased delivery of bile acids to the colon could potentially increase the risk of colorectal cancer, although long-term studies in patients with similar conditions (e.g., after partial ileal bypass) have not shown an increased incidence. [1]
The depletion of bile acids by Elobixibat could theoretically alter the cholesterol-to-bile acid ratio in bile, potentially increasing the risk of cholesterol gallstone formation. [1]

[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.

---

Drug Indication
Treatment of chronic constipation

---

Elobixibat is a first-in-class, orally administered ileal bile acid transporter (IBAT) inhibitor developed for the treatment of chronic idiopathic constipation (CIC). [1]
Its mechanism of action involves local inhibition of bile acid reabsorption in the ileum, leading to increased delivery of bile acids to the colon. In the colon, bile acids stimulate motility and secretion, resulting in accelerated colonic transit, looser stools, and improved constipation symptoms. [1]
By inhibiting ileal reabsorption, Elobixibat upregulates hepatic synthesis of new bile acids from cholesterol, which may lead to beneficial effects on serum lipid profiles, such as lowering LDL cholesterol. [1]
Clinical trials have demonstrated its efficacy in increasing spontaneous bowel movements, loosening stool consistency, reducing straining, and accelerating colonic transit within the first week of treatment, with effects sustained for at least 8 weeks. [1]
Its low systemic absorption contributes to a generally favorable safety profile with primarily gastrointestinal side effects (abdominal pain, diarrhea), which are often dose-related and considered an extension of its pharmacological effect. [1]
As of the publication date (2013), Elobixibat had not been submitted for regulatory approval in any country and Phase III trials were anticipated. [1]

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

182.77

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)

配方 1 中的溶解度: ≥ 2.08 mg/mL (2.99 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 20.8 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

---

配方 2 中的溶解度: 2.08 mg/mL (2.99 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 悬浊液; 超声助溶。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

---

View More

配方 3 中的溶解度: ≥ 2.08 mg/mL (2.99 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

---

请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。