In patch clamp hERG tests, betrixaban (PRT054021) exhibits an IC50 of 8.9 μM[1]. Betrixaban exhibits an IC50 and a Ki for plasma kallikrein of 6.3 μM and 3.5 μM, respectively[1]. Compared to all other drugs (hERG Ki⩽0.5 μM), betrixaban (hERG Ki 1.8 μM) shows noticeably less hERG activity[1]. Betrixaban inhibits the production of thrombin (5–25 ng/mL)[3].

在膜片钳 hERG 测试中，betrixaban (PRT054021) 的 IC50 为 8.9 μM[1]。 Betrixaban 对血浆激肽释放酶的 IC50 和 Ki 分别为 6.3 μM 和 3.5 μM[1]。与所有其他药物 (hERG Ki⩽0.5 μM) 相比，betrixaban (hERG Ki 1.8 μM) 显示出明显较低的 hERG 活性[1]。 Betrixaban 抑制凝血酶的产生 (5–25 ng/mL)[3]。

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在全血凝血酶原酶抑制实验中，Betrixaban显示出剂量依赖性的对血小板介导的凝血酶原酶活性的抑制，这与其作为直接FXa抑制剂的作用机制一致。
在组织因子诱导的凝血酶生成实验中，浓度为5–25 ng/mL的Betrixaban对凝血酶生成的抑制程度，与磺达肝癸钠2.5 mg达到的谷浓度和峰浓度水平相当。
使用膜片钳技术的临床前毒理学研究表明，Betrixaban不是hERG钾通道的强效抑制剂（IC50 = 8.9 μM）。其hERG IC50与人体预期峰血浆浓度的比值提供了30倍的安全边际，防止了显著的hERG通道抑制。 [3]

在犬中，贝曲西班的口服生物利用度为 51.6%（0.5 mg/kg，静脉注射；2.5 mg/kg，口服）[1]。在猴子中，贝曲西班的口服生物利用度为 58.7%（0.75 mg/kg，静脉注射；7.5 mg/kg，口服）[1]。 R-Antidote 可逆转贝曲西班介导的全血 INR 升高。 30 分钟静脉输注后，贝曲西班的总血浆浓度为 0.2±0.01 μM，其中 40%±7.2% 的抑制剂保持未结合。 r-Antidote 递送后，未结合抑制剂的比例下降至 0.3%±0.1%，而总血浆浓度上升至 2.0±0.4 μM[2]。当用于棉线上血栓积聚的兔腹部腔静脉模型时，贝曲西班 (3 mg/kg) 对血栓质量的抑制作用与依诺肝素 1.6 mg/kg 几乎相同（76% 与 96% 抑制作用）[3]。在大鼠颈动脉的氯化铁损伤模型中，贝曲西班 (19.1 mg/kg) 至少与依诺肝素 7.6 mg/kg 和氯吡格雷 3 mg/kg/d 一样有效（90% vs. 70% vs. 80% 通畅率）分别）保持通畅[3]。

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在兔腹部下腔静脉血栓形成模型中，3 mg/kg剂量的Betrixaban对血栓质量的抑制（76%）与依诺肝素1.6 mg/kg（96%）几乎相当。
在啮齿动物氯化铁颈动脉损伤模型中，19.1 mg/kg的Betrixaban在维持动脉通畅性方面（90%）至少与依诺肝素7.6 mg/kg（70%）和氯吡格雷3 mg/kg/天（80%）同样有效。
在狒狒动静脉分流血栓形成模型中，Betrixaban显示出对静脉侧和动脉侧放射性标记血小板沉积的剂量依赖性抑制。0.05–0.49 mg/kg的剂量范围产生的血浆浓度为7–83 ng/mL，导致分流静脉侧血小板沉积抑制30%–90%。 [3]

使用体外凝血实验评估了Betrixaban的抗凝作用及机制。在全血中，测量了其抑制凝血酶原酶活性（将凝血酶原转化为凝血酶的复合物）的能力，显示出剂量依赖性的抑制。
在血浆中进行了组织因子诱导的凝血酶生成实验。将Betrixaban以指定浓度（5–25 ng/mL）加入，测量随时间推移对凝血酶生成的抑制，并与标准剂量磺达肝癸钠的效果进行比较。
使用重组酶进行酶学测定，确定了Betrixaban对因子Xa的抑制常数（Ki）和半数抑制浓度（IC50）。Betrixaban显示出对FXa的强效和选择性抑制。 [3]

1 mg/kg; oral
Rats

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The antithrombotic efficacy of Betrixaban was evaluated in three animal models. In the rabbit abdominal vena cava model, thrombus formation was induced on cotton threads, and drugs were administered intravenously. In the rodent ferric chloride carotid artery injury model, thrombosis was induced by topical application of ferric chloride, and drugs were administered. In the baboon AV shunt model, an external shunt was placed between the femoral artery and vein, and platelet deposition was monitored using radiolabeled platelets after intravenous drug administration. Specific drug formulation details were not provided. [3]

Absorption, Distribution and Excretion
Bectraxaban is rapidly absorbed at an 80 mg dose. Peak plasma concentrations are reached within 3–4 hours after oral administration in healthy individuals. Oral bioavailability is 34%, which decreases with food intake. Specifically, compared to a fasting state, Cmax and AUC are reduced by an average of 70% and 61% after a low-fat meal, and by 50% and 48%, respectively, after a high-fat meal. This effect remains significant up to 6 hours after food intake. Bectraxaban is reported to be primarily excreted via the gastrointestinal tract; studies have shown that up to 85% of bectraxaban is excreted in feces, with only 11% excreted in urine. The apparent volume of distribution is 32 L/kg. The renal clearance of bectraxaban is extremely low (only 5–7% of the administered dose). Metabolism/Metabolites One of the key characteristics of bectraxaban is its extremely low hepatic metabolism (<1%), thus avoiding drug accumulation that may occur in cases of hepatic impairment. In human plasma, the unchanged betracitabine is the predominant form, followed by two inactive metabolites independent of CYP hydrolases (15-18%). Due to minimal hepatic metabolism, drug interactions with CYP450 inhibitors or agonists are unlikely.

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Biological Half-Life
Btraxaban has a relatively long half-life, ranging from 19 to 27 hours.

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In healthy volunteers, after oral administration of 80 mg betracitabine, btraxaban is rapidly absorbed, reaching peak plasma concentration (Tmax) within 3-4 hours.
Oral bioavailability is 34%. Concurrent intake of fatty foods reduces peak concentration (Cmax) and area under the curve (AUC) by approximately 50%.
Approximately 60% of betracitabine is bound to plasma proteins.
Btraxaban is primarily excreted unchanged in the feces via the hepatobiliary route (82%–89% of the administered dose), possibly mediated by the P-glycoprotein (P-gp) efflux pump. Renal clearance is extremely low, accounting for only 5%–7% of the oral dose. Bectroxaban is minimally metabolized in the liver by cytochrome P450 (CYP450) enzymes (<1%) and does not induce or inhibit CYP450. The terminal elimination half-life (t1/2) is 37 hours. The effective half-life of bectroxaban (the time required for its anticoagulant effect to decrease by 50%) is approximately 20 hours. The plasma peak-to-trough concentration ratio of bectroxaban is low. [3]

Hepatotoxicity
In the registration study, 1% to 2% of patients treated with betraxaban experienced serum transaminase levels exceeding 3 times the upper limit of normal (ULN), a similar proportion was observed in the control group treated with enoxaparin. Similarly, 0.6% of the control group treated with betraxaban experienced transaminase levels exceeding 5 times the ULN, and 0.4% of the control group treated with enoxaparin experienced this. Probability score: E (Unproven but suspected rare cause of clinically significant liver injury). Use during pregnancy and lactation ◉ Overview of use during lactation
Btraxaban has been discontinued in the United States. Since there is currently no information regarding the use of betraxaban during lactation, and the drug is orally absorbed, alternative medications are recommended, especially for breastfed newborns or preterm infants. ◉ Effects on breastfed infants
As of the revision date, no relevant published information was found.
◉ Effects on Lactation and Breast Milk
As of the revision date, no relevant published information was found.

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Protein Binding
Betradix baniform has been reported to have a protein binding rate of approximately 60%.

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The main toxic risk of anticoagulants is bleeding. In the Phase II clinical trial, the incidence of clinically relevant bleeding was lower in the betroxaban group than in the control group (enoxaparin or warfarin). In the EXPLORE-Xa trial, the incidence of gastrointestinal adverse events (including diarrhea, nausea, dyspepsia, and vomiting) was higher in the betroxaban group (especially the 80 mg dose group) compared to warfarin. Most adverse events were mild. No significant signs of hepatotoxicity were observed. In the Phase II study, the incidence of elevated alanine aminotransferase (>3 times the upper limit of normal) was no higher in the betroxaban group than in the control group, and the elevation was transient. No cases of elevated bilirubin were reported. Although betraxaban is derived from a class of compounds with hERG channel inhibitory potential, comprehensive QTc interval studies in healthy volunteers and ECG monitoring in clinical trials have shown that betraxaban (up to a single dose of 140 mg) does not cause clinically significant QTc interval prolongation exceeding regulatory thresholds. As a substrate for P-gp, co-administration with potent P-gp inhibitors (such as ketoconazole) can increase plasma concentrations of betraxaban by approximately two-fold. [3]

[1]. Discovery of Betrixaban (PRT054021), N-(5-chloropyridin-2-yl)-2-(4-(N,N-dimethylcarbamimidoyl)benzamido)-5-methoxybenzamide, a highly potent, selective, and orally efficacious factor Xa inhibitor. Bioorg Med Chem Lett. 2009 Apr 15;19(8):21.

[2]. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med. 2013 Apr;19(4):446-51.

[3]. Profile of betrixaban and its potential in the prevention and treatment of venous thromboembolism. Vasc Health Risk Manag. 2015 Jun 26;11:343-51.

Bectrazaban is a secondary amide compound formed by the condensation of the carboxyl group of 4-(N,N-dimethylcarbamoylimino)benzoic acid and the amino group of 2-amino-N-(5-chloropyridin-2-yl)-5-methoxybenzamide. It is a synthetic anticoagulant that targets factor Xa, the activating factor in the coagulation cascade. It is both an anticoagulant and an EC 3.4.21.6 (coagulation factor Xa) inhibitor. It belongs to the guanidine, benzamide, secondary amide, monochloropyridine, and monomethoxybenzene classes. Bectrazaban is a non-vitamin K antagonist oral anticoagulant whose mechanism of action is through competitive and reversible inhibition of factor Xa. Its low affinity for hERG channels while maintaining its factor Xa inhibitory ability has made it stand out among all lead compounds. Betrixaban, currently developed by Portola Pharmaceuticals Inc., is used to prevent VTE in adult patients with moderate to severe activity limitations or other risks of venous thromboembolism (VTE). VTE, which can manifest as deep vein thrombosis or pulmonary embolism, is one of the leading causes of preventable death in hospitalized patients. Betrixaban is a factor Xa inhibitor. Its mechanism of action is as a factor Xa inhibitor. Betrixaban is an oral anticoagulant and a direct inhibitor of factor Xa, used to reduce the risk of deep vein thrombosis and pulmonary embolism in patients hospitalized for acute illness at high risk of venous thrombosis. Betrixaban is associated with a lower incidence of elevated serum transaminases during treatment, but has not been found to be associated with clinically significant liver injury. Betrixaban is an orally effective inhibitor of coagulation factor Xa (activating factor X) with anticoagulant activity. Betrixaban is primarily excreted unchanged in bile, with a half-life of approximately 19 hours.

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Drug Indications
Bectroxaban is indicated for the prevention of VTE in patients with moderate to severe activity limitations or those meeting the risk criteria for venous thromboembolism (VTE).

FDA Label

Prevention of Venous Thromboembolism

Prevention of Venous Thromboembolism

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Mechanism of Action
Bectroxaban is a cofactor-independent direct inhibitor of factor Xa, inhibiting both free and prothrombin-bound factor Xa.Pharmacodynamics
Bectroxaban is an oral anticoagulant whose mechanism of action is through the inhibition of thrombin production without directly affecting platelet aggregation.Bectroxaban is an oral, direct, and selective factor Xa (FXa) inhibitor.
Its most notable pharmacological characteristics are minimal renal excretion, minimal hepatic metabolism via CYP450, and a long half-life (approximately 37 hours).
It has been evaluated in a phase II clinical trial for the prevention of venous thromboembolism after total knee arthroplasty (EXPERT trial) and for the prevention of stroke in patients with atrial fibrillation (EXPLORE-Xa trial).
A phase III clinical trial (APEX) is currently underway to evaluate the efficacy of long-term betraxaban (80 mg once daily for 35–42 days) versus short-term enoxaparin in the prevention of venous thromboembolism in high-risk patients with acute severe medical conditions.
Betraxaban is expected to be used in patients with severe renal insufficiency (creatinine clearance <30 mL/min), who are typically excluded from trials of other novel oral anticoagulants (NOACs).
There is currently no approved antidote. Btraxaban. Its long half-life may pose problems in cases of bleeding or requiring emergency surgery, however, an antidote (andasanetine α) is currently under joint development. [3]

C23H22CLN5O3

451.91

451.141

330942-05-7

Betrixaban-d6;2098655-51-5;Betrixaban maleate;936539-80-9;Betrixaban hydrochloride;2099719-47-6

10275777

Light yellow to yellow solid powder

1.3±0.1 g/cm3

200-212 ºC

1.629

2.93

110.9

3

5

7

32

668

0

XHOLNRLADUSQLD-UHFFFAOYSA-N

InChI=1S/C23H22ClN5O3/c1-29(2)21(25)14-4-6-15(7-5-14)22(30)27-19-10-9-17(32-3)12-18(19)23(31)28-20-11-8-16(24)13-26-20/h4-13,25H,1-3H3,(H,27,30)(H,26,28,31)

N-(5-Chloropyridin-2-yl)-2-((4-(N,N-dimethylcarbamimidoyl)benzoyl)amino)-5- methoxybenzamide

PRT054021; PRT-021; MK-4448; MLN-1021; PRT 054021; PRT-054021; MK4448; MLN 1021; PRT 021; PRT021; MK 4448; MLN1021; trade name Bevyxxa

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)

配方 1 中的溶解度: ≥ 2.5 mg/mL (5.53 mM) (饱和度未知) in 10% DMSO + 40% PEG300 +5% Tween-80 + 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 25.0 mg/mL澄清DMSO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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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。