IP Receptor ( EC50 = 1.9 nM ); TP Receptor ( EC50 = 919 nM ); IP Receptor ( Ki = 32.1 nM ); IP Receptor ( Ki = 4680 nM );
DP/DP1 Receptor:0.6 nM (EC50); IP Receptor:1.9 nM (EC50); EP2 Receptor:6.2 nM (EC50) ; EP3 Receptor:68.9 nM (EC50) ; EP4 Receptor:181 nM (EC50) ; EP1 Receptor:285 nM (EC50) ; TP Receptor:919 nM (EC50) ; EP2 Receptor:3.6 nM (Ki) ; EP1 Receptor:212 nM (Ki); EP4 Receptor:826 nM (Ki); EP3 Receptor:2505 nM (Ki); DP/DP1 Receptor:4.4 nM (Ki) ; IP Receptor:32.1 nM (Ki) ; FP Receptor:4680 nM (Ki)

曲前列环素对 DP1、EP2 和 IP 受体具有高亲和力（Ki 分别为 4.4、3.6 和 32 nM），对 EP1 和 EP4 受体亲和力低，对 EP3、FP 和 TP 受体亲和力更低。与曲前列环素一样，IP、DP1 和 EP2 受体的激活均可导致人肺动脉血管舒张[1]。曲前列环素抑制培养的内皮集落形成细胞的活力。来自曲前列环素预处理的间充质干细胞的条件培养基刺激内皮集落形成细胞增殖[5]。

吸入曲前列环素钠是一种前列环素类似物，是最新获得 FDA 批准用于治疗致命孤儿疾病：肺动脉高压 (PAH) 的药物[2]。与安慰剂相比，曲前列环素可保留窦内皮细胞内层并减少移植后早期血小板沉积。安慰剂组肝组织血流明显受损，而曲前列环素则维持与正常水平相似的血流[3]。曲前列环素治疗显着增加裸鼠基质胶中内皮集落形成细胞联合间充质干细胞的血管形成能力。沉默间充质干细胞中的 VEGF-A 基因也会阻断曲前列环素的促血管生成作用[4]。曲前列环素在提高小鼠和人类造血干细胞和祖细胞的细胞内 cAMP 水平方面最有效[5]。与常氧小鼠相比，曲前列环素治疗显着减少了细胞的募集。曲前列环素还可降低右心室收缩压并略微减少血管重塑，但无法逆转右心室肥厚[6]。

将来自人类或小鼠的造血干细胞和祖细胞在 37°C 下在载体存在下或与 10 μM 曲前列环素和 30 μM 毛喉素联合培养一小时和二十四小时。细胞凋亡试剂盒用于在 4°C 下用磷酸盐缓冲盐水洗涤细胞后对细胞进行外化磷脂酰丝氨酸染色 [5]。

Rats: For the study, male Lewis rats weighing between 200 and 300 g are employed. 24 hours prior to hepatectomy, donor animals are given treprostinil or a placebo, and the corresponding recipient animal receives the same care until the moment of sacrifice. Treatment is invisible to the surgeon. To study what happens right after IRI, recipients are sacrificed 1, 3, 6, 24 and 48 hours after transplantation. Using an Alzet implantable osmotic pump, subcutaneous administration of treprostinil (100 ng/kg/min) or placebo is performed. This dosage is chosen to produce a plasma concentration that is steady-state and falls between 5 and 20 ng/mL[3].
Mice: Mice that have had bone marrow transplantation (BMT) are split up into five groups, each with six to ten mice. In a normobaric chamber, one group of mice is exposed to hypoxia (10% inspired oxygen fraction), while the other group of mice (control BMT) spends 28 days in a normoxic chamber with a normal oxygen environment (21% inspired O₂ fraction). While the two other groups of mice receive four weeks of hypoxic exposure and receive Treprostinil infusions at varying dose levels (14 ng/kg and 70 ng/kg per minute), the sham group mice receive saline treatment. Comparatively, infusion rates for humans in PAH therapy range from 10 to 60 ng/kg per minute[6].

Absorption, Distribution and Excretion
After subcutaneous infusion, treprostinil is completely absorbed, with a bioavailability of about 100%, and it reaches steady-state concentrations in approximately 10 hours. The pharmacokinetics of treprostinil follow a two-compartment model and are linear between 2.5 and 125 ng/kg/min. Subcutaneous and intravenous doses of treprostinil are bioequivalent at 10 ng/kg/min. Compared to healthy subjects, patients with mild and moderate hepatic insufficiency had a corresponding Cmax 2- and 4-times higher and an AUC0-∞ 3- and 5-times higher when given a subcutaneous treprostinil dose of 10 ng/kg/min for 150 min. When given orally at doses between 0.5 and 15 mg twice a day, treprostinil follows a dose-proportional pharmacokinetic profile. The oral bioavailability of treprostinil is 17%, and drug concentration reaches its highest level between 4 and 6 hours after oral administration. The oral absorption of treprostinil is affected by food. The AUC and Cmax of oral treprostinil increase 49% and 13%, respectively, when this drug is administered with a high-fat, high-calorie meal. The AUC and Cmax of inhaled treprostinil were proportional to the doses administered (18 to 90 μg). The bioavailability of inhaled treprostinil was 64% in patients receiving 2 doses of 18 μg, and 72% in patients receiving two doses of 36 μg. Two separate studies that evaluated the pharmacokinetics of inhaled treprostinil at a maintenance dose of 54 μg found that the mean Cmax was 0.91 and 1.32 ng/mL, respectively, with a corresponding Tmax of 0.25 and 0.12 hr and a mean AUC of 0.81 and 0.97 hr⋅ng/mL.
Treprostinil metabolites are excreted through urine (79%) and feces (13%) over 10 days. Only a small proportion of treprostinil is excreted unchanged. When administered orally, 1.13% and 0.19% of unchanged treprostinil diolamine are found in urine and feces, respectively. When administered subcutaneously, intravenously or by inhalation, 4% of unchanged treprostinil is found in urine.
The volume of distribution of treprostinil is 14 L/70 kg.
The clearance of treprostinil is 30 L/hr in a 70 kg person. In patients with mild to moderate hepatic insufficiency, clearance is reduced up to 80%.

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Metabolism / Metabolites
Treprostinil is mostly metabolized by the liver, mainly by CYP2C8, and by CYP2C9 to a lesser extent. Treprostinil does not have a single major metabolite. The five metabolites detected in urine (HU1 through HU5) accounted for 13.8, 14.3, 15.5, 10.6 and 10.2% of the dose, respectively. One of the metabolites (HU5) is the glucuronide conjugate of treprostinil. HU1, HU2, HU3 and HU4 are formed through the oxidation of the 3-hydroxyloctyl side chain. None of the metabolites of treprostinil appear to be active. _In vitro_ studies suggest that treprostinil does not inhibit or induce any major CYP enzymes.

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Biological Half-Life
The terminal elimination half-life of treprostinil is approximately 4 hours, following a two-compartment model.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
One patient taking treprostinil breastfed her infant for one year without any complications. However, until more data are available, treprostinil should only be used with careful monitoring during breastfeeding.
◉ Effects in Breastfed Infants
A woman developed pulmonary artery hypertension and was treated with intravenous treprostinil beginning at 32 weeks of gestation and titrated up to 26 ng/kg/min. The dose was nearly doubled postpartum because of worsening symptoms. She breastfed (extent not stated) her infant for one year with no apparent drug-related problems, although there was concern for obesity at 6 months of age. The infant was healthy and developing normally at 2 years of age.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
At _in vitro_ concentrations ranging from 330 to 10,000 μg/L, the human plasma protein binding of treprostinil is approximately 91%. This concentration is above what is considered to be clinically relevant.

[1]. Binding and activity of the prostacyclin receptor (IP) agonists, treprostinil and iloprost, at human prostanoid receptors: treprostinil is a potent DP1 and EP2 agonist. Biochem Pharmacol. 2012 Jul 1;84(1):68-75.

[2]. Treprostinil indirectly regulates endothelial colony forming cell angiogenic properties by increasing VEGF-A produced by mesenchymal stem cells. Thromb Haemost. 2015 Oct;114(4):735-47.

[3]. Inhaled treprostinil sodium for the treatment of pulmonary arterial hypertension. Expert Opin Pharmacother. 2011 Nov;12(16):2583-93.

[4]. Repurposing Treprostinil for Enhancing Hematopoietic Progenitor Cell Transplantation. Mol Pharmacol. 2016 Jun;89(6):630-44.

[5]. Treprostinil, a prostacyclin analog, ameliorates ischemia-reperfusion injury in rat orthotopic liver transplantation. Am J Transplant. 2011 Nov;11(11):2508-16.

[6]. Treprostinil inhibits the recruitment of bone marrow-derived circulating fibrocytes in chronic hypoxic pulmonary hypertension. Eur Respir J. 2010 Dec;36(6):1302-14.

Treprostinil is a carboxylic acid and a carbotricyclic compound. It has a role as a platelet aggregation inhibitor, a vasodilator agent, an antihypertensive agent, a cardiovascular drug, a vitamin K antagonist and a human blood serum metabolite.
Treprostinil is a stable tricyclic analogue of prostacyclin that promotes the vasodilation of pulmonary and systemic arterial vascular beds and the inhibition of platelet aggregation. It reduces symptoms in patients with pulmonary arterial hypertension (PAH) and pulmonary hypertension associated with interstitial lung disease. The first agent approved for the treatment of PAH was [epoprostenol], a synthetic prostacyclin that significantly increases patients' quality of life. However, the use of epoprostenol is limited due to its short half-life (3-5 min) and instability at room temperature. The use of more stable alternatives such as treprostinil provides patients with PAH with more treatment options. Treprostinil was approved by the FDA in 2002 for the treatment of pulmonary arterial hypertension. It is available in the following routes of administration: subcutaneous, intravenous, inhaled and oral. The first generic form of treprostinil became available in 2019.
Treprostinil is a Prostacycline Vasodilator. The physiologic effect of treprostinil is by means of Vasodilation.
See also: Treprostinil Sodium (has salt form); Treprostinil Diolamine (is active moiety of); Treprostinil Palmitil (is active moiety of).

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Drug Indication
The FDA has indicated treprostinil for the treatment of pulmonary arterial hypertension and pulmonary hypertension associated with interstitial lung disease to improve exercise ability. It is also used to treat pulmonary arterial hypertension in patients requiring transition from epoprostenol. The Health Canada label specifies that treprostinil is indicated for the long-term treatment of pulmonary arterial hypertension in NYHA Class III and IV patients who did not respond adequately to conventional therapy. L24244
Treatment of adult patients with WHO Functional Class (FC) III or IV and: inoperable chronic thromboembolic pulmonary hypertension (CTEPH), orpersistent or recurrent CTEPH after surgical treatmentto improve exercise capacity.
Treatment of pulmonary arterial hypertension

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Mechanism of Action
Treprostinil is a stable analogue of prostacyclin, a prostaglandin that acts as an anti-thrombotic agent and a potent vasodilator. Prostacyclin analogues are useful in the treatment of pulmonary arterial hypertension (PAH), a disease characterized by abnormally high blood pressure in the arteries between the heart and lungs. PAH leads to right heart failure due to the remodelling of pulmonary arteries, and patients with this condition have a poor prognosis. Treprostinil binds and activates the prostacyclin receptor, the prostaglandin D2 receptor 1, and the prostaglandin E2 receptor 2. The activation of these receptors leads to the elevation of intracellular cyclic adenosine monophosphate (cAMP) levels, which consequently promotes the opening of calcium-activated potassium channels that lead to cell hyperpolarization. This mechanism promotes the direct vasodilation of pulmonary and systemic arterial vascular beds and the inhibition of platelet aggregation. In addition to its direct vasodilatory effects, treprostinil inhibits inflammatory pathways.

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Pharmacodynamics
As an analogue of prostacyclin, treprostinil promotes the vasodilation of pulmonary and systemic arterial vascular beds and the inhibition of platelet aggregation. In animals, the vasodilatory effects of treprostinil lead to a reduction of right and left ventricular afterload and an increase in cardiac output and stroke volume. Treprostinil also causes a dose-related negative inotropic and lusitropic effect, and no major effects on cardiac conduction have been detected. Short-lasting effects on QTc were detected in healthy volunteers (n=240) given inhaled single doses of 54 and 84 μg of treprostinil. These effects dissipated rapidly as treprostinil concentrations lowered. When given subcutaneously or intravenously, treprostinil has the potential to reach higher concentrations. The effect of oral treprostinil on QTc has not been evaluated. Due to its ability to inhibit platelet aggregation, treprostinil can increase the risk of bleeding, and patients with low systemic arterial pressure taking treprostinil may experience symptomatic hypotension. The abrupt withdrawal of treprostinil or drastic changes in dose may worsen the symptoms of pulmonary arterial hypertension (PAH). The inhalation of treprostinil can also cause bronchospasms in patients with asthma, chronic obstructive pulmonary disease (COPD), or bronchial hyperreactivity. When given intravenously, treprostinil can lead to infusion complications and increase the risk of bloodstream infections.

C23H34O5

412.49500

390.24

C, 70.74; H, 8.78; O, 20.48

81846-19-7

Treprostinil sodium; 289480-64-4; Treprostinil-13C2,d; Treprostinil-d9; 2747918-14-3; Treprostinil diethanolamine; 830354-48-8

6918140

White to yellow oily liquid or solid

1.158g/cm3

587.1ºC at 760mmHg

121-123°

199.3ºC

1.553

2.248

89.82

3

5

10

28

495

5

C([C@H]1[C@H](O)C[C@@H]2CC3C(OCC(=O)O)=CC=CC=3C[C@H]12)C[C@@H](O)CCCCC

PAJMKGZZBBTTOY-ZFORQUDYSA-N

InChI=1S/C23H34O5/c1-2-3-4-7-17(24)9-10-18-19-11-15-6-5-8-22(28-14-23(26)27)20(15)12-16(19)13-21(18)25/h5-6,8,16-19,21,24-25H,2-4,7,9-14H2,1H3,(H,26,27)/t16-,17-,18+,19-,21+/m0/s1

2-[[(1R,2R,3aS,9aS)-2-hydroxy-1-[(3S)-3-hydroxyoctyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[g]naphthalen-5-yl]oxy]acetic acid

LRX15; LRX 15; LRX-15; UT15; UT-15; UT 15; BW 15AU; Uniprost; TU-62840; reprostinil; Orenitram; Remodulin; Tyvaso; LRX-15; UT-15;

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: ≥ 125 mg/mL (~320.1 mM)

配方 1 中的溶解度: ≥ 2.08 mg/mL (5.33 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 (5.33 mM) (饱和度未知) 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), 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 (5.33 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;
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