Trisodium;2-[[2-[bis(carboxylatomethyl)amino]-3-[(4,4-diphenylcyclohexyl)oxy-oxidophosphoryl]oxypropyl]-[2-[bis(carboxylatomethyl)amino]ethyl]amino]acetate;gadolinium(3+);hydrate | 193901-90-5

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: Trisodium;2-[[2-[bis(carboxylatomethyl)amino]-3-[(4,4-diphenylcyclohexyl)oxy-oxidophosphoryl]oxypropyl]-[2-[bis(carboxylatomethyl)amino]ethyl]amino]acetate;gadolinium(3+);hydrate
• CAS: 193901-90-5
• 化学式: C33H40GdN3Na3O15P
• 分子量: 975.9
• InChiKey: PIZALBORPSCYJU-UHFFFAOYSA-H

物化性质

• 密度：
  1.1224 g/mL at 25 °C
• 粘度：
  3.0 cP at 20 °C

计算性质

• 辛醇/水分配系数(LogP)：
  -15.37
• 重原子数：
  56
• 可旋转键数：
  18
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  270
• 氢给体数：
  1
• 氢受体数：
  18

ADMET

代谢

Gadofosveset在人体内不会发生可测量的代谢。

Gadofosveset does not undergo measurable metabolism in humans.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

静脉注射后，钆夫酸二钠与内源性血清白蛋白可逆结合，使得其血管内停留时间比非蛋白结合对比剂更长。与血清白蛋白的结合还增加了钆夫酸二钠的磁共振弛豫率，并减少了水分子质子的弛豫时间（T1），从而使得血液的信号强度（亮度）增加。

Following intravenous injection, gadofosveset binds reversibly to endogenous serum albumin resulting in longer vascular residence time than non-protein binding contrast agents. The binding to serum albumin also increases the magnetic resonance relaxivity of gadofosveset and decreases the relaxation time (T1) of water protons resulting in an increase in signal intensity (brightness) of blood.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

识别：Gadofosveset被指示用作磁共振血管造影（MRA）的对比剂，用于评估成人已知或疑似外周血管疾病的腹股沟闭塞性疾病（AIOD）。人类暴露和毒性：在临床试验中，Ablavar给药后45分钟，观察到QTc从基线变化的平均增加（2.8毫秒）；在24小时和72小时没有观察到增加。在Ablavar给药后45分钟，39/702（6%）的患者观察到QTc从基线变化30至60毫秒。在这个时间点，3/702（0.4%）的患者经历了QTc增加>60毫秒。这些QTc延长没有与心律失常或症状相关。对于因QTc延长而有心律失常高风险的患者（例如，同时用药，潜在的心脏状况），考虑获取基线心电图以帮助评估Ablavar给药的风险。如果给这些患者施用Ablavar，考虑在大部分Ablavar从血液中消除之前进行随访心电图和风险降低措施（例如，患者咨询或强化心电图监测）。在肾功能正常的患者中，大部分Ablavar在注射后72小时内从血液中消除。Ablavar可能引起过敏性或/和过敏性反应，包括危及生命或致命的反应。在临床试验中，1676名受试者中有两名出现了过敏性或/和过敏性反应。在802名接受0.03 mmol/kg Ablavar的受试者中，常见的不良反应是瘙痒、头痛、恶心、血管扩张、感觉异常、注射部位瘀伤、味觉异常、灼热感、静脉穿刺部位瘀伤、高血压、头晕（不包括眩晕）、感觉冷。动物研究：发育或生殖毒性/在生殖研究中，怀孕的大鼠和家兔以各种剂量接受gadofosveset三钠，直至大约11倍（大鼠）和21.5倍（家兔）的人类剂量（基于体表面积）。最高剂量在两种物种中都导致了母体毒性。在家兔接受3倍人类剂量（基于体表面积）的gadofosveset三钠时，观察到着床后损失、吸收和死胎增加。在大鼠或家兔后代中没有观察到胎儿异常。因为怀孕动物接受了ABLAVAR的重复每日剂量，它们的总体暴露量显著高于单次给予人类的剂量。

IDENTIFICATION: Gadofosveset is indicated for use as a contrast agent in magnetic resonance angiography (MRA) to evaluate aortoiliac occlusive disease (AIOD) in adults with known or suspected peripheral vascular disease. HUMAN EXPOSURE AND TOXICITY: In clinical trials, a small increase (2.8 msec) in the average change from baseline in QTc was observed at 45 minutes following Ablavar administration; no increase was observed at 24 and 72 hours. A QTc change of 30 to 60 msec from baseline was observed in 39/702 (6%) patients at 45 min following Ablavar administration. At this time point, 3/702 (0.4%) patients experienced a QTc increase of > 60 msec. These QTc prolongations were not associated with arrhythmias or symptoms. In patients at high risk for arrhythmias due to QTc prolongation (e.g., concomitant medications, underlying cardiac conditions) consider obtaining baseline electrocardiograms to help assess the risks for Ablavar administration. If Ablavar is administered to these patients, consider follow-up electrocardiograms and risk reduction measures (e.g., patient counseling or intensive electrocardiography monitoring) until most Ablavar has been eliminated from the blood. In patients with normal renal function, most Ablavar was eliminated from the blood by 72 hours following injection. Ablavar may cause anaphylactoid and/or anaphylactic reactions, including life-threatening or fatal reactions. In clinical trials, anaphylactoid and/or anaphylactic reactions occurred in two of 1676 subjects. Common adverse reactions in 802 subjects receiving Ablavar at 0.03 mmol/kg are pruritis headache, nausea, vasodilatation, paresthesia injection site bruising, dysgeusia, burning sensation, venipuncture site bruise, hypertension, dizziness (excluding vertigo), feeling cold. ANIMAL STUDIES: Developmental or Reproductive Toxicity/ In reproductive studies, pregnant rats and rabbits received gadofosveset trisodium at various doses up to approximately 11 (rats) and 21.5 (rabbits) times the human dose (based on body surface area). The highest dose resulted in maternal toxicity in both species. In rabbits that received gadofosveset trisodium at 3 times the human dose (based on body surface area), increased post-implantation loss, resorptions, and dead fetuses were observed. Fetal anomalies were not observed in the rat or rabbit offspring. Because pregnant animals received repeated daily doses of ABLAVAR, their overall exposure was significantly higher than that achieved with a single dose administered to humans.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

ABLAVAR 注射剂已对人类使用的剂量高达0.15 mmol/kg（临床剂量的5倍）。临床试验中没有报告 ABLAVAR 过量。一旦发生过量，治疗应直接针对支持所有生命功能，并立即实施对症治疗。已经证明，使用高通量透析程序进行血液透析可以去除Gadofosveset。

ABLAVAR Injection has been administered to humans up to a dose of 0.15 mmol/kg (5 times the clinical dose). No ABLAVAR overdoses were reported in clinical trials. In the event of an overdose, direct treatment toward the support of all vital functions and prompt institution of symptomatic therapy. Gadofosveset has been shown to be removed by hemodialysis using a high flux dialysis procedure.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 立即急救：确保已经进行了充分的中毒物清除。如果患者停止呼吸，开始人工呼吸，最好使用需求阀复苏器、袋阀面罩装置或口袋面罩，按训练操作。如有必要，执行心肺复苏。立即用缓慢流动的水冲洗受污染的眼睛。不要催吐。如果发生呕吐，让患者前倾或置于左侧（如果可能的话，头部向下）以保持呼吸道畅通，防止吸入。保持患者安静，维持正常体温。寻求医疗帮助。 /毒物A和B/

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 基本治疗：建立专利气道（如有需要，使用口咽或鼻咽气道）。如有必要，进行吸痰。观察呼吸不足的迹象，如有需要，辅助通气。通过非循环呼吸面罩以10至15升/分钟的速度给予氧气。监测肺水肿，如有必要，进行治疗……。监测休克，如有必要，进行治疗……。预防癫痫发作，如有必要，进行治疗……。对于眼睛污染，立即用水冲洗眼睛。在运输过程中，用0.9%的生理盐水（NS）持续冲洗每只眼睛……。不要使用催吐剂。对于摄入，如果患者能吞咽、有强烈的干呕反射且不流口水，则用温水冲洗口腔，并给予5毫升/千克，最多200毫升的水进行稀释……。在去污染后，用干燥的无菌敷料覆盖皮肤烧伤……。/毒药A和B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

钆弗塞特主要通过尿液排出，注射剂量的79%至94%（平均83.7%）在尿液中回收。在尿液中回收的钆弗塞特总量中，有94%在最初的72小时内回收。钆弗塞特剂量的较小部分在粪便中回收（大约4.7%）。

Gadofosveset is eliminated primarily in the urine, with between 79% and 94% (mean of 83.7%) of an injected dose recovered in the urine. Of the total gadofosveset recovered in urine, 94% is recovered within the first 72 hours. A small portion of gadofosveset dose is recovered in feces (approximately 4.7%).

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

稳态下钆酸fosveset的平均分布体积为148 +/- 16 mL/kg，大约相当于细胞外液的体积。循环中的钆酸fosveset有相当一部分与血浆蛋白结合，主要是白蛋白。在注射0.03 mmol/kg后的0.05、0.5、1和4小时内，钆酸fosveset的血浆蛋白结合率在79.8%到87.4%之间。

The mean volume of distribution at steady state for gadofosveset was 148 +/- 16 mL/kg, roughly equivalent to that of extracellular fluid. A significant portion of circulating gadofosveset is bound to plasma proteins, predominantly albumin. At 0.05, 0.5, 1 and 4 hours after injection of 0.03 mmol/kg the plasma protein binding of gadofosveset ranges from 79.8 to 87.4%.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

静脉给药的钆酸fosveset的药代动力学符合双室开放模型，平均血浆浓度（报告为平均值+/- SD）在注射后3分钟为0.43 +/- 0.04 mmol/L，在注射后1小时为0.24 +/- 0.03 mmol/L。分布相的平均半衰期为0.48 +/- 0.11小时，消除相的平均半衰期为16.3 +/- 2.6小时。给予0.03 mmol/kg的钆酸fosveset后，平均总清除率为6.57 +/- 0.97 mL/h/kg。

The pharmacokinetics of intravenously administered gadofosveset conforms to a two-compartment open model with mean plasma concentrations (reported as mean +/-SD) of 0.43 +/- 0.04 mmol/L at 3 minutes post-injection, and 0.24 +/- 0.03 mmol/L at one hour post-injection. The mean half-life of the distribution phase is 0.48 +/- 0.11 hours and the mean half-life of the elimination phase is 16.3 +/- 2.6 hours. The mean total clearance of gadofosveset is 6.57 +/- 0.97 mL/h/kg following the administration of 0.03 mmol/kg.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在动物研究中，高达0.3毫摩尔/千克的剂量下，不到1%的加朵fosveset被分泌到哺乳大鼠的乳汁中。

In animal studies, less than 1% of gadofosveset at doses up to 0.3 mmol/kg was secreted in the milk of lactating rats.

来源:Hazardous Substances Data Bank (HSDB)