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

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]。

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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]

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]

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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]。

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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]

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

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。

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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。

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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。

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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。