Eovist | 135326-22-6

• 物质功能分类: 有机原料 - 羧酸类化合物及衍生物
• 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: Eovist
• 英文别名: disodium;2-[[2-[bis(carboxylatomethyl)amino]-3-(4-ethoxyphenyl)propyl]-[2-[bis(carboxylatomethyl)amino]ethyl]amino]acetate;gadolinium(3+)
• CAS: 135326-22-6
• 化学式: C23H28GdN3Na2O11
• 分子量: 725.7
• InChiKey: SLYTULCOCGSBBJ-UHFFFAOYSA-I

物化性质

• 溶解度：
  溶于二甲基亚砜
• 密度：
  1.088 g/mL at 37 °C
• 粘度：
  2.32 mPa.s at 37 °C

计算性质

• 辛醇/水分配系数(LogP)：
  -13.34
• 重原子数：
  40
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  220
• 氢给体数：
  0
• 氢受体数：
  14

ADMET

代谢

硫酸钆二钠不被代谢。

Gadoxetate disodium is not metabolized.

来源:Hazardous Substances Data Bank (HSDB)

代谢

硫酸钆二钠不被代谢。

Gadoxetate disodium is not metabolized.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

鉴定：钆塞酸二钠是一种基于钆的对比剂，用于成人已知或疑似局灶性肝脏疾病的T1加权磁共振成像（MRI）肝脏检查以检测和表征病变。人类暴露和毒性：使用EOVIST最常见的（大于或等于0.5%）不良反应是恶心、头痛、感觉热、头晕和背痛。肝脏病变患者接受了钆塞酸二钠增强的肝脏磁共振成像（MRI）。记录并评估了不良事件（AEs），以考虑潜在的药物关系。对有特殊病史的患者进行了亚组分析。分析了来自上市后安全监测的全球自发AEs和不良反应（ADRs）。临床开发计划共纳入了1989名患者。共有1581/1989（79.5%）的患者接受了最终批准的剂量，即0.025毫摩尔/千克体重。10.1%的患者报告了AEs，其中4.1%被归类为相关AEs。恶心和头痛是最常见报告的相关AEs，每种各占1.1%。年龄、对比剂过敏史、肝硬化或肝肾功能受损并没有显著影响AEs的发生率和类型。上市后安全监测数据库涵盖了超过220万名患者。恶心是最常见的ADR，报告率为0.00652%；所有其他症状的报告率低于0.004%。用于肝脏MRI的钆塞酸二钠具有极好的安全性能。钆塞酸二钠相关的短暂严重呼吸运动伪影在20毫升给药（2毫升/秒）后明显更常见，并且在慢性阻塞性肺病患者中显著更频繁发生。体积相关效应表明非过敏性样机制。动物研究：在单次给予EOVIST的狗中观察到与剂量相关的QTc增加，给药后30分钟内解决。当给予等于或大于0.1毫摩尔/千克（是人类剂量的2.2倍）的剂量时，注意到QTc增加。在最高剂量达到0.5毫摩尔/千克（是人类剂量的11倍）时，QTcF的最大增加值等于或小于20毫秒。在大鼠和家兔中进行了动物生殖和发育毒性研究。在器官形成期间给予怀孕大鼠的钆塞酸二钠静脉注射，在高达推荐人类单剂量的32倍（按mmol/m2计算）的剂量下，未表现出致畸性。然而，在3.2倍人类剂量（按mmol/m2计算）时，注意到着床前损失增加。与未处理的对照组相比，当怀孕的家兔接受26倍推荐人类单剂量的钆塞酸二钠时，着床后损失和吸收率增加，窝大小减少。这种情况发生在没有母体毒性证据的情况下。因为怀孕的动物接受了重复的每日剂量的EOVIST，它们的总体暴露量显著高于人类标准单次给药所达到的暴露量。

IDENTIFICATION: Gadoxetate disodiumis a gadolinium-based contrast agent indicated for intravenous use in T1-weighted magnetic resonance imaging (MRI) of the liver to detect and characterize lesions in adults with known or suspected focal liver disease. HUMAN EXPOSURE AND TOXICITY: The most frequent (>/=0.5%) adverse reactions associated with the use of EOVIST are nausea, headache, feeling hot, dizziness, and back pain. Patients with liver lesions received gadoxetate disodium-enhanced liver magnetic resonance imaging (MRI). Adverse events (AEs) were recorded and evaluated with regard to a potential drug relationship. Subgroup analyses were run on patients with special medical history. Worldwide spontaneous AEs and adverse drug reactions (ADRs) from postmarketing safety surveillance were analyzed. A total of 1989 patients were included in the clinical development program. A total of 1581/1989 (79.5%) patients received the finally approved dose of 0.025 mmol/kg body weight. 10.1% of patients reported AEs, 4.1% were classified as related AEs. Nausea and headache were the most frequently reported related AEs, with 1.1% each. Age, history of contrast media allergy, liver cirrhosis, or impaired liver or renal function did not significantly impact the frequency and type of AEs. The postmarketing safety surveillance database encompassed more than 2.2 million patients. Nausea was the most frequent ADR, with a reporting rate of 0.00652%; all other symptoms were below 0.004%. Gadoxetate disodium for liver MRI has an excellent safety profile Gadoxetate disodium-associated transient severe respiratory motion artifact is significantly more common after 20-mL administration (2 mL/s) and occurs significantly more often in patients with chronic obstructive pulmonary disease. The volume-related effect suggests a nonallergiclike mechanism. ANIMAL STUDIES: A dose-related increase in QTc which was resolved by 30 minutes post dosing was observed in dogs when given a single dose of EOVIST. The increase was noted when given in doses equal to or greater than 0.1 mmol/kg (2.2 times the human dose). Maximum increase in QTcF was equal to or less than 20 ms at doses up to 0.5 mmol/kg (11 times the human dose). Animal reproductive and developmental toxicity studies were done in rats and rabbits. Gadoxetate disodium was not teratogenic when given intravenously during organogenesis to pregnant rats at doses up to 32 times the recommended single human dose (mmol/m2 basis). However, an increase in preimplantation loss was noted at 3.2 times the human dose (mmol/m2 basis). Compared to untreated controls, rates of postimplantation loss and absorption increased and litter size decreased when pregnant rabbits received gadoxetate disodium at doses 26 times the recommended human single dose (mmol/m2 basis). This occurred without evidence of maternal toxicity. Because pregnant animals received repeated daily doses of EOVIST, their overall exposure was significantly higher than that achieved with the standard single dose administered to humans.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

在健康受试者中进行的一项相互作用研究中，OATP抑制剂红霉素与EOVIST联合使用对EOVIST的疗效和药代动力学没有影响。没有进行与其他药物的临床相互作用研究。

An interaction study in healthy subjects demonstrated that the co-administration of the OATP inhibitor erythromycin did not influence efficacy and pharmacokinetics of EOVIST. No further clinical interaction studies with other medicinal products have been performed.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

患有肝损伤的患者接受了钆塞酸二钠增强的肝脏磁共振成像（MRI）。记录并评估了不良事件（AEs），以考虑可能的药物关系。对有特殊医疗史的患者进行了亚组分析。分析了全球自发的不良事件和药品不良反应（ADRs）的上市后安全监测数据。共有1989名患者被纳入临床开发计划。共有1581/1989（79.5%）的患者接受了最终批准的剂量，即0.025毫摩尔/千克体重。10.1%的患者报告了不良事件，4.1%被归类为相关不良事件。恶心和头痛是最常报告的相关不良事件，每种各占1.1%。年龄、对比剂过敏史、肝硬化或肝肾功能受损并没有显著影响不良事件的频率和类型。上市后安全监测数据库涵盖了超过220万名患者。恶心是最常见的不良反应，报告率为0.00652%；所有其他症状的报告率低于0.004%。用于肝脏MRI的钆塞酸二钠具有极好的安全性能。

Patients with liver lesions received gadoxetate disodium-enhanced liver magnetic resonance imaging (MRI). Adverse events (AEs) were recorded and evaluated with regard to a potential drug relationship. Subgroup analyses were run on patients with special medical history. Worldwide spontaneous AEs and adverse drug reactions (ADRs) from postmarketing safety surveillance were analyzed. A total of 1989 patients were included in the clinical development program. A total of 1581/1989 (79.5%) patients received the finally approved dose of 0.025 mmol/kg body weight. 10.1% of patients reported AEs, 4.1% were classified as related AEs. Nausea and headache were the most frequently reported related AEs, with 1.1% each. Age, history of contrast media allergy, liver cirrhosis, or impaired liver or renal function did not significantly impact the frequency and type of AEs. The postmarketing safety surveillance database encompassed more than 2.2 million patients. Nausea was the most frequent ADR, with a reporting rate of 0.00652%; all other symptoms were below 0.004%. Gadoxetate disodium for liver MRI has an excellent safety profile.

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

二钠戈达克酸通过肾脏和肝胆途径等量消除。在22至39岁的健康志愿者中观察到的二钠戈达克酸（0.01至0.1毫摩尔/千克）的平均终末消除半衰期为0.91至0.95小时。清除率似乎随年龄增长而略有下降。在0.4毫升/千克（0.1毫摩尔/千克）的剂量下，即推荐剂量的4倍时，药代动力学呈剂量线性。

Gadoxetate disodium is equally eliminated via the renal and hepatobiliary routes. The mean terminal elimination half-life of gadoxetate disodium (0.01 to 0.1 mmol/kg) has been observed in healthy volunteers of 22-39 years of age to be 0.91 to 0.95 hour. Clearance appeared to decrease slightly with increasing age. The pharmacokinetics are dose-linear up to a dose of 0.4 mL/kg (0.1 mmol/kg), which is 4 times the recommended dose.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

静脉给药后，二钠戈达克斯酸的血药浓度-时间曲线呈现双指数下降。二钠戈达克斯酸在稳态时的总体分布体积约为0.21 L/kg（细胞外空间）；血浆蛋白结合率小于10%。二钠戈达克斯酸不会通过完整的血脑屏障，并且可以通过胎盘屏障扩散。

After intravenous administration, the plasma concentration time profile of gadoxetate disodium is characterized by a bi-exponential decline. The total distribution volume of gadoxetate disodium at steady state is about 0.21 L/kg (extracellular space); plasma protein binding is less than 10%. Gadoxetate disodium does not pass the intact blood-brain barrier and diffuses through the placental barrier.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在给予0.1毫摩尔/千克[153Gd]钆塞酸二钠的哺乳期大鼠中，通过母体乳汁转移到幼崽的总放射性活性的比例不到0.5%，大多数在2小时内。

In lactating rats given 0.1 mmol/kg [153Gd] gadoxetate disodium, less than 0.5% of the total administered radioactivity was transferred to the neonates via maternal milk, mostly within 2 hours.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

二钠戈达克酸通过肾脏和肝胆途径等量消除。在22至39岁的健康志愿者中观察到的二钠戈达克酸（0.01至0.1毫摩尔/千克）的平均终末消除半衰期为0.91至0.95小时。清除率似乎随年龄增长而略有下降。在0.4毫升/千克（0.1毫摩尔/千克）的剂量下，即推荐剂量的4倍时，药代动力学呈剂量线性。

Gadoxetate disodium is equally eliminated via the renal and hepatobiliary routes. The mean terminal elimination half-life of gadoxetate disodium (0.01 to 0.1 mmol/kg) has been observed in healthy volunteers of 22-39 years of age to be 0.91 to 0.95 hour. Clearance appeared to decrease slightly with increasing age. The pharmacokinetics are dose-linear up to a dose of 0.4 mL/kg (0.1 mmol/kg), which is 4 times the recommended dose.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

静脉给药后，二钠戈达克斯酸的血药浓度-时间曲线呈现双指数下降。二钠戈达克斯酸在稳态时的总体分布体积约为0.21 L/kg（细胞外空间）；血浆蛋白结合率小于10%。二钠戈达克斯酸不会通过完整的血脑屏障，并且可以通过胎盘屏障扩散。

After intravenous administration, the plasma concentration time profile of gadoxetate disodium is characterized by a bi-exponential decline. The total distribution volume of gadoxetate disodium at steady state is about 0.21 L/kg (extracellular space); plasma protein binding is less than 10%. Gadoxetate disodium does not pass the intact blood-brain barrier and diffuses through the placental barrier.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335

制备方法与用途

肝脏特异性MR造影剂 钆塞酸二钠（Gd-EOB-DTPA）

钆塞酸二钠，简称 Gd-EOB-DTPA，是由德国先灵公司开发的新型肝脏特异性 MR 造影剂。该造影剂显著提高了 T1 加权 MRI 对肝内病灶的检出率，并结合了强化初期动态 T1 加权 MR 的表现，进一步提升了对肝内病灶定性诊断的准确性。2008 年 7 月，美国 FDA 已批准其用于临床。

用途

钆塞酸二钠可用于检测肝脏局灶性病变，在 T1 加权磁共振成像中提供病灶特征信息。

药效学

Gd-EOB-DTPA 是一种肝脏 T1 加权 MRI 的顺磁性对比剂。它易于被肝细胞吸收，从而增强健康肝组织的影像（即肝实质影像增强）。然而，当肝细胞功能缺失或受损时（如囊肿、转移瘤和大多数肝细胞癌），这些区域则不会显像，从而使它们更容易被检测与定位。此外，Gd-EOB-DTPA 还有助于区分良性与恶性肝损伤。

应用前景

随着 Gd-EOB-DTPA 在国内外的广泛应用，其应用范围已从单纯诊断肝内局限性病变扩展至评估肝弥漫性病变（如非酒精性脂肪性肝病、胆汁淤积性肝病、肝纤维化和肝硬化等），并在预测肝功能及肝移植后肝功能不全等方面展现出优势。然而，其具体价值仍需进一步的临床研究加以验证。

生物活性

Gadoxetate 是一种含有顺磁钆的造影剂，通常以甘露醇二钠形式通过静脉注射给药。