Endogenous Metabolite

ω-3脂肪酸可降低甘油三酯（TG）水平，但低密度脂蛋白胆固醇（LDL-C）水平的相应增加可能会影响心血管风险升高患者实现脂质目标。AMR101是一种研究药物，含有≥96%的纯二十碳五烯酸乙酯。III期多中心、安慰剂对照、随机、双盲、12周开放标签扩展研究（MARINE）调查了AMR101在229名TG水平非常高（≥500mg/dl）的患者中的疗效和安全性。AMR101 4 g/天显著降低了安慰剂调整后的TG水平中位数，与基线相比降低了33.1%（p<0.0001），AMR101 2 g/天降低了TG水平19.7%（p=0.0051）。LDL-C的变化很小，不显著。AMR101可以在不增加LDL-C水平的情况下显著降低TG。[1]

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甲状腺激素影响几乎所有脂质代谢途径的反应。据报道，甲状腺功能减退症患者的血浆游离脂肪酸（FFA）浓度通常在正常范围内。然而，在这项研究中，我们发现一些甲状腺功能减退症患者的血浆FFA浓度高于正常范围。这些患者的甲状腺功能障碍症状比血浆游离脂肪酸浓度较低的患者轻。根据这些发现，我们假设FFA浓度的变化一定与甲状腺功能有关。然后，我们使用动物模型研究了高纯度二十碳五烯酸乙酯（EPA-E）对1-甲基-2-咪唑硫醇（MMI）诱导的甲状腺功能减退大鼠甲状腺功能的影响，EPA-E是一种来源于鱼油的n-3多不饱和脂肪酸。口服EPA-E抑制了MMI诱导的甲状腺功能减退大鼠甲状腺激素水平的降低和甲状腺滤泡的变化。这些发现表明，FFA可能影响甲状腺功能，EPA-E可能预防MMI诱导的甲状腺功能减退[2]

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ω-3脂肪酸改善脂肪代谢的确切机制尚不完全清楚。本研究旨在确定二十碳五烯酸（EPA）乙酯给药对参与脂肪生成和脂肪酸氧化途径的几种肌肉、肝脏和脂肪组织基因表达水平的影响。喂食标准饮食（对照动物）或高脂肪饮食的雄性Wistar大鼠每天口服EPA乙酯（1g/kg）灌胃治疗5周。高脂饮食导致血浆胆固醇水平显著升高（P<0.01），EPA可逆转这一现象（P<0.001）。EPA治疗组的循环甘油三酯水平也显著降低（P<0.05）。EPA给药诱导了一些脂肪生成基因的显著下调，如肌肉乙酰辅酶a羧化酶β（ACCβ）（P<0.05）和肝脏脂肪酸合酶（FAS）（P<.05）。此外，在喂食对照饮食的EPA处理动物中观察到葡萄糖激酶（GK）基因表达的降低（P<0.01），而在喂食高脂肪饮食的组中发现GK mRNA水平显著升高。另一方面，在EPA处理组中没有发现参与β氧化的基因发生改变，如乙酰辅酶A合酶4（ACS4）、乙酰辅酶A合成酶5（ACS5）或乙酰辅酶A氧化酶（ACO）。令人惊讶的是，与预期相反，在EPA治疗后，观察到肝脏PPARalpha的表达水平显著降低（P<0.01）。这些发现表明，EPA乙酯处理能够下调参与脂肪酸合成的一些基因，而不影响β氧化相关基因的转录激活[3]。

Twenty-nine male Wistar rats (6 weeks old) were housed in a temperature-controlled room (22±2°C) with a 12-h light–dark cycle. Animals were distributed into four experimental groups: control, control+EPA (CEPA), overweight and overweight+EPA (OEPA). All animals were maintained for an adaptation period of 4 days, fed chow diet and given deionized water ad libitum. After this period of time, the control and CEPA groups were fed a standard pelleted diet containing 76% carbohydrates, 6% lipids and 18% proteins (362 kcal/100 g). On the other hand, the overweight and OEPA groups were fed a cafeteria diet composed of the following items: paté, chips, bacon, chocolate, biscuits and pelleted diet (relative ratio, 2:1:1:1:1:1). The composition of this diet was as follows: 9% energy as protein, 29% energy as carbohydrate and 62% energy as lipid, by dry weight. All animals had ad libitum access to water and food for 5 weeks. The fatty acid composition of both control and high-fat diets was analyzed as previously reported, with the finding that both control and cafeteria diets have no EPA. Thus, the rats' only source of this fatty acid is oral gavage. Thus, the CEPA and OEPA groups were treated, simultaneously with the maintenance of diets for 35 days, with 1g/kg animal weight of highly purified EPA ethyl ester. This dose of EPA ethyl ester has been previously reported by Nobukata et al. to have a beneficial effect on diabetes prevention. The same volume of water was orally administrated to the control and overweight groups, as previously described in other studies, for 35 days. These control and overweight groups without treatment with any other type of fatty acid (such as saturated fatty acids with equal chain length as EPA or oleic acid) are more likely to be considered as control groups in our study design. This is because it has been demonstrated that supplementation with some other fatty acids is able to modify adiposity and circulating levels of biochemical and hormonal markers planned to be determined in the present study. [3]

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Five-week-old male Wistar rats were used in the exper- iments described in this study. The rats were divided into two groups of six on the basis of their initial body weights. Hypothyroidism in rats was induced by sub- cutaneous injection of MMI at a daily dose of 1 mg with con- comitant oral administration of Eicosapentaenoic Acid Ethyl Ester/EPA-E at a daily dose of 300 mg/kg (or the same volume of saline as a control) for 4 weeks. After 4 weeks the rats were anesthetized with chloroform and blood samples and thyroid tissues were obtained. Part of the thyroid tissues were immediately frozen in liquid nitrogen and stored at 80 C until use. [2]

Absorption, Distribution and Excretion
Icosapent ethyl is de-esterfied, converted into active EPA, and then absorbed in the small intestine. It reaches peak plasma concentration in 5 hours post-oral administration. Very little (<1%) is left circulating in the plasma as EPA incorporates into phospholipids, TG's, and cholesteryl esters.
Icosapent ethyl is not renally excreted
Steady state volume of distribution of active EPA is 88 L
Total plasma clearance, EPA = 684 mL/hr

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Metabolism / Metabolites
Once converted into active EPA, it is hepatically metabolized into acetyl Coenzyme A via beta-oxidation.

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Biological Half-Life
The half life of EPA is 89 hours.

9831415 rat LD50 oral >20 gm/kg Yakkyoku. Pharmacy., 41(1621), 1990
9831415 rat LD50 intraperitoneal 15 gm/kg Yakkyoku. Pharmacy., 41(1621), 1990
9831415 rat LD50 subcutaneous >20 gm/kg Yakkyoku. Pharmacy., 41(1621), 1990
9831415 mouse LD50 oral >20 gm/kg Yakkyoku. Pharmacy., 41(1621), 1990
9831415 mouse LD50 intraperitoneal >20 gm/kg Yakkyoku. Pharmacy., 41(1621), 1990

[1]. Jacobson TA. A new pure ω-3 eicosapentaenoic acid ethyl ester (AMR101) for the management of hypertriglyceridemia: the MARINE trial. Expert Rev Cardiovasc Ther. 2012 Jun;10(6):687-695.

[2]. Effect of eicosapentaenoic acid ethyl ester on hypothyroid function. J Endocrinol. 2001 Nov;171(2):259-65.

[3]. Down-regulation in muscle and liver lipogenic genes: EPA ethyl ester treatment in lean and overweight (high-fat-fed) rats. J Nutr Biochem. 2009 Sep;20(9):705-14.

Ethyl (5Z,8Z,11Z,14Z,17Z)-icosapentaenoate is a long-chain fatty acid ethyl ester resulting from the formal condensation of the carboxy group of (5Z,8Z,11Z,14Z,17Z)-icosapentaenoic acid with the hydroxy group of ethanol. It has a role as an anticholesteremic drug, a marine metabolite, an antipsychotic agent, an antidepressant and a prodrug. It is a long-chain fatty acid ethyl ester and a polyunsaturated fatty ester. It is functionally related to an all-cis-5,8,11,14,17-icosapentaenoic acid.
Icosapent ethyl or ethyl eicosapentaenoic acid is a synthetic derivative of the omega-3 fatty acid eicosapentaenoic acid (EPA). It is used as an adjunct therapy for severe hypertriglyceridemia (TG levels > 500 mg/dL) and to reduce the risk of cardiovascular events in certain patients with elevated triglycerides. FDA approved on July 26, 2012.
Icosapent Ethyl is a highly purified omega-3 fatty acid that can decrease serum triglyceride levels. Icosapent ethyl reduces serum triglycerides without an increase in LDL cholesterol, but increases the cholesterol and triglyceride content in skeletal muscle.
See also: Icosapent (has active moiety).

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Drug Indication
Icosapent ethyl is indicated as an adjunct to maximally tolerated statin therapy to reduce the risk of myocardial infarction, stroke, coronary revascularization, and unstable angina requiring hospitalizing in adult patients with elevated triglycerides (≥150 mg/dL) and established cardiovascular disease or who have diabetes mellitus and ≥2 other risk factors for cardiovascular disease. It is also indicated as an adjunct to diet to reduce triglyceride levels in adult patients with severe (≥500 mg/dL) hypertriglyceridemia.
FDA Label
Indicated to reduce cardiovascular risk as an adjunct to statin therapy.
Treatment of hypertriglyceridaemia

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Mechanism of Action
Studies suggest that EPA reduces hepatic very low-density lipoprotein triglycerides (VLDL-TG) synthesis and/or secretion and enhances TG clearance from circulating VLDL particles. Potential mechanisms of action include increased β-oxidation; inhibition of acyl-CoA:1,2-diacylglycerol acyltransferase (DGAT); decreased lipogenesis in the liver; and increased plasma lipoprotein lipase activity.

C22H34O2

330.512

330.255

C, 79.95; H, 10.37; O, 9.68

86227-47-6

Eicosapentaenoic Acid;10417-94-4;Eicosapentaenoic acid ethyl ester-d5;1392217-44-5

9831415

Colorless to light yellow liquid

0.9±0.1 g/cm3

417.0±34.0 °C at 760 mmHg

103.1±24.0 °C

0.0±1.0 mmHg at 25°C

1.496

7.32

26.3

0

2

15

24

425

0

C(/CCCC(=O)OCC)=C/C/C=C\C/C=C\C/C=C\C/C=C\CC

SSQPWTVBQMWLSZ-AAQCHOMXSA-N

InChI=1S/C22H34O2/c1-3-5-6-7-8-9-10-11-12-13-14-15-16-17-18-19-20-21-22(23)24-4-2/h5-6,8-9,11-12,14-15,17-18H,3-4,7,10,13,16,19-21H2,1-2H3/b6-5-,9-8-,12-11-,15-14-,18-17-

ethyl (5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenoate

Eicosapentaenoic Acid Ethyl Ester; Epadel; Miraxion; AMR-101; EPA-E; LAX-101; ethyl icosapentate; 86227-47-6; ICOSAPENT ETHYL; Eicosapentaenoic acid ethyl ester; Epadel; ethyl eicosapentaenoate; Vascepa; Timnodonic acid ethyl ester; EPA E; LAX 101; MND 21; MND-21; AMR 101; AMR101; MND21; EPAE; LAX101

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中（例如氮气保护），避免吸湿/受潮。

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~302.57 mM)
Ethanol : ~50 mg/mL (~151.29 mM)

配方 1 中的溶解度: ≥ 5 mg/mL (15.13 mM) (饱和度未知) in 10% EtOH + 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，将 100 μL 50.0 mg/mL 澄清乙醇储备液加入到 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: 5 mg/mL (15.13 mM) (饱和度未知) in 10% EtOH + 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 50.0 mg/mL 澄清乙醇储备液加入到 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: ≥ 5 mg/mL (15.13 mM) (饱和度未知) in 10% EtOH + 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 50.0 mg/mL 澄清 EtOH 储备液添加到 900 μL 玉米油中并充分混合。

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配方 4 中的溶解度: 2.5 mg/mL (7.56 mM) 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), 悬浊液; 超声助溶。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL 澄清的 DMSO 储备液加入到400 μL PEG300中，混匀；再向上述溶液中加入50 μL Tween-80，混匀；然后加入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 5 中的溶解度: 2.5 mg/mL (7.56 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100μL 25.0mg/mL澄清的DMSO储备液加入到900μL 20％SBE-β-CD生理盐水中，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 6 中的溶解度: ≥ 2.5 mg/mL (7.56 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 25.0 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。