2-[2-[Carboxylatomethyl-[2-[carboxylatomethyl(carboxymethyl)amino]ethyl]amino]ethyl-(carboxymethyl)amino]-3-phenylmethoxypropanoate;gadolinium(3+);6-(methylamino)hexane-1,2,3,4,5-pentol | 113662-23-0

• 物质功能分类: 医药中间体
• 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: 2-[2-[Carboxylatomethyl-[2-[carboxylatomethyl(carboxymethyl)amino]ethyl]amino]ethyl-(carboxymethyl)amino]-3-phenylmethoxypropanoate;gadolinium(3+);6-(methylamino)hexane-1,2,3,4,5-pentol
• 英文别名: 2-[2-[carboxylatomethyl-[2-[carboxylatomethyl(carboxymethyl)amino]ethyl]amino]ethyl-(carboxymethyl)amino]-3-phenylmethoxypropanoate;gadolinium(3+);6-(methylamino)hexane-1,2,3,4,5-pentol
• CAS: 113662-23-0
• 化学式: C36H62GdN5O21
• 分子量: 1058.1
• InChiKey: OCDAWJYGVOLXGZ-UHFFFAOYSA-K

物化性质

• 颜色/状态：
  Hygroscopic powder
• 熔点：
  124 °C
• 溶解度：
  Freely soluble in water
• 密度：
  1.22 g/mL at 20 °C
• 旋光度：
  Specific optical rotation: -26.9 deg at 20 °C/365 °C (c = 1.45 in water)
• 粘度：
  9.2 mPa.sec at 20 °C; 5.3 mPa.sec at 37 °C

计算性质

• 辛醇/水分配系数(LogP)：
  -14.26
• 重原子数：
  63
• 可旋转键数：
  27
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.69
• 拓扑面积：
  446
• 氢给体数：
  14
• 氢受体数：
  26

ADMET

代谢

未检测到钆酸苯妥离子的生物转化。体内钆酸苯妥离子的解离已被证明是最小的，仅有不到1%的自由螯合剂单独在粪便中被回收。

There was no detectable biotransformation of gadobenate ion. Dissociation of gadobenate ion in vivo has been shown to be minimal, with less than 1% of the free chelating agent being recovered alone in feces.

来源:Hazardous Substances Data Bank (HSDB)

代谢

未检测到钆喷酸离子发生生物转化。体内钆喷酸离子的解离已被证明是最小的，粪便中单独回收的自由螯合剂少于1%。

There was no detectable biotransformation of gadobenate ion. Dissociation of gadobenate ion in vivo has been shown to be minimal, with less than 1% of the free chelating agent being recovered alone in feces.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

鉴定和使用：钆贝酸二甲基葡糖胺（多哈斯）是一种用于磁共振成像研究的对比剂，以无色至略带黄色的水溶液形式提供，仅供静脉使用。人类暴露和毒性：钆基对比剂（GBCAs）会增加药物消除功能受损患者的肾源性系统性纤维化（NSF）的风险。除非诊断信息至关重要且无法通过无对比剂的MRI或其他方式获得，否则应避免在这些患者中使用GBCAs。NSF可能导致致命或致残的系统性纤维化，影响皮肤、肌肉和内脏器官。NSF的风险在以下患者中最高：慢性严重肾病或急性肾损伤。筛查患者是否有急性肾损伤和其他可能降低肾功能的情况。对于存在长期肾功能降低风险的患者（60岁以上、高血压或糖尿病患者），通过实验室检测估算肾小球滤过率（GFR）。对于NSF风险最高的患者，不要超过推荐的多哈斯剂量，并在再次给药前留出足够的时间以消除药物。已报告过过敏性反应和类过敏性反应，涉及心血管、呼吸和/或皮肤表现。有些患者出现循环衰竭并死亡。在临床试验中接受多哈斯的患者中观察到了心律失常。通过培养的人淋巴细胞染色体畸变试验研究了钆贝酸二甲基葡糖胺的致突变潜力。该剂在存在和不存在代谢激活的情况下，在任何处理中均未增加异常细胞或多倍体细胞的发病率。因此，可以得出结论，在这些实验条件下，钆贝酸二甲基葡糖胺未显示出致裂变或多倍体诱导活性。动物研究：通过对一系列毒理学安全性研究的支持，钆贝酸二甲基葡糖胺用于临床作为血管内磁共振成像对比剂。在啮齿类和非啮齿类动物中进行了单次和多次剂量毒性、生殖和致突变性评估。猴子最初的临床不良反应与人类0.1 mmol/kg钆贝酸二甲基葡糖胺后的系统暴露量高出34倍有关。在重复剂量毒性研究中观察到良好的系统耐受性。在伴有血脑屏障损伤的局部脑缺血实验条件下，钆贝酸二甲基葡糖胺在剂量甚至高达最大临床剂量（0.3 mmol/kg）的10倍时仍能良好耐受。在大鼠中，后代的生殖性能、身体和行为发育未受到影响。然而，在器官形成期（第6天至第18天）以2 mmol/kg/天（基于体表面积是人类剂量的6倍）静脉给药时，多哈斯在大兔中显示出致畸性，导致3只不同胎儿的3个胎儿出现小眼/小眼睛和/或局部视网膜折叠。此外，以3 mmol/kg/天（基于体表面积是人类剂量的10倍）静脉给药的多哈斯在大兔中增加了宫内死亡。致突变性测试排除了钆贝酸二甲基葡糖胺的任何遗传毒性潜力。以下遗传毒性研究的结果为阴性：1）体外细菌反向突变试验，2）体外哺乳动物细胞基因突变试验，3）体外染色体畸变试验，4）体外非计划DNA合成试验，以及5）大鼠体内微核试验。

IDENTIFICATION AND USE: Gadobenate dimeglumine (MultiHance) is a contract agent for MRI studies, supplied as a colorless to slightly yellow, aqueous solution intended for intravenous use only. HUMAN EXPOSURE AND TOXICITY: Gadolinium-based contrast agents (GBCAs) increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of GBCAs in these patients unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. NSF may result in fatal or debilitating systemic fibrosis affecting the skin, muscle and internal organs. The risk for NSF appears highest among patients with: chronic, severe kidney disease, or acute kidney injury. Screen patients for acute kidney injury and other conditions that may reduce renal function. For patients at risk for chronically reduced renal function (older than 60 years, hypertension or diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing. For patients at highest risk for NSF, do not exceed the recommended MultiHance dose and allow a sufficient period of time for elimination of the drug from the body prior to re-administration. Anaphylactic and anaphylactoid reactions have been reported, involving cardiovascular, respiratory, and/or cutaneous manifestations. Some patients experienced circulatory collapse and died. Cardiac arrhythmias have been observed in patients receiving MultiHance in clinical trials. The mutagenic potential of gadobenate dimeglumine was studied by the chromosome aberration test in cultured human lymphocytes. The agent induced no increase in the incidence of aberrant cells or polyploid cells in any treatments both in the presence and absence of metabolic activation. Thus, it is concluded that gadobenate dimeglumine has shown no evidence of clastogenic or polyploidy-inducing activity under these experimental conditions. ANIMAL STUDIES: To support the clinical use of gadobenate dimeglumine for injection as an intravascular magnetic resonance imaging contrast medium through an extensive battery of toxicological safety studies. Single and multiple dose toxicity, reproduction and mutagenicity assessments were carried out in rodents and non-rodents. Initial adverse clinical signs in monkeys were associated with a systemic exposure 34 times higher than that found in humans after 0.1 mmol/kg gadobenate dimeglumine. Good systemic tolerance was observed in repeated dose toxicity studies. In experimental conditions of focal brain ischemia associated with blood-brain barrier lesions, gadobenate dimeglumine was well tolerated up to doses even 10 times higher than the maximum clinical dose (0.3 mmol/kg) intended for brain imaging procedures. Reproductive performance and physical and behavioral development of offspring were unaffected in rats. However, MultiHance has been shown to be teratogenic in rabbits when given intravenously administered at 2 mmol/kg/day (6 times the human dose based on body surface area) during organogenesis (day 6 to 18) inducing microphthalmia/small eye and/or focal retinal fold in 3 fetuses from 3 separate litters. In addition, MultiHance intravenously administered at 3 mmol/kg/day (10 times the human dose based on body surface area) has been shown to increase intrauterine deaths in rabbits. Mutagenicity tests excluded any genotoxic potential of gadobenate dimeglumine. The results were negative in the following genetic toxicity studies: 1) in vitro bacteria reverse mutation assays, 2) an in vitro gene mutation assay in mammalian cells, 3) an in vitro chromosomal aberration assay, 4) an in vitro unscheduled DNA synthesis assay, and 5) an in vivo micronucleus assay in rats.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

多潘立酮和其他药物可能会竞争胆管多特异性有机阴离子转运体（MOAT，也称为MRP2或ABCC2）。因此，多潘立酮可能会延长顺铂、蒽环类药物（例如多柔比星、柔红霉素）、长春碱类（例如长春新碱）、甲氨蝶呤、依托泊苷、他莫昔芬和紫杉醇等药物的系统性暴露时间。特别是，需要考虑MOAT活性降低的患者（例如杜宾-约翰逊综合症）药物暴露时间延长的可能性。

MultiHance and other drugs may compete for the canalicular multispecific organic anion transporter (MOAT also referred to as MRP2 or ABCC2). Therefore MultiHance may prolong the systemic exposure of drugs such as cisplatin, antracyclines (e.g. doxorubicin, daunorubicin), vinca alkaloids (e.g. vincristine), methotrexate, etoposide, tamoxifen, and paclitaxel. In particular, consider the potential for prolonged drug exposure in patients with decreased MOAT activity (e.g. Dubin Johnson syndrome).

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)

毒理性

• 解毒与急救

/SRP:/ 高级治疗：对于昏迷、严重肺水肿或严重呼吸困难的病人，考虑进行口咽或鼻咽气管插管以控制气道。使用带气囊的面罩进行正压通气技术可能有益。考虑使用药物治疗肺水肿……。对于严重的支气管痉挛，考虑给予β激动剂，如沙丁胺醇……。监测心率和必要时治疗心律失常……。开始静脉输注5%葡萄糖水（D5W），保持通路开放，最低流量/ SRP: "To keep open", minimal flow rate /. 如果出现低血容量的迹象，使用0.9%生理盐水（NS）或乳酸钠林格氏液（LR）。对于伴有低血容量迹象的低血压，谨慎给予液体。注意液体过载的迹象……。用地西泮或劳拉西泮治疗癫痫……。使用丙美卡因氢氯化物协助眼部冲洗……。/毒物A和B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

钆贝酸根离子具有快速的分布半衰期（报告为平均值±标准差），为0.084±0.012至0.605±0.072小时。中心室的分布体积范围从0.074±0.017至0.158±0.038 L/kg，而通过面积估算的分布体积范围从0.170±0.016至0.282±0.079 L/kg。后者的估算大约相当于人体细胞外平均体液量。体外研究表明，钆贝酸根离子与人类血清蛋白没有显著结合。/钆贝酸根离子/

Gadobenate ion has a rapid distribution half-life (reported as mean + or - SD) of 0.084 + or - 0.012 to 0.605 + or - 0.072 hours. Volume of distribution of the central compartment ranged from 0.074:: 0.017 to 0.158 :: 0.038 L/kg, and estimates of volume of distribution by area ranged from 0.170+ or - 0.016 to 0.282+ or - 0.079 L/kg. These latter estimates are approximately equivalent to the average volume of extracellular body water in man. In vitro studies showed no appreciable binding of gadobenate ion to human serum proteins. /Gadobenate ion/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

... 对非标记的钆贝酸二甲基葡胺在大鼠、兔、狗和猴子体内的药代动力学进行了评估，并为了生物分布研究，使用了（153）-Gd标记的钆贝酸二甲基葡胺。通过高效液相色谱、X射线荧光光谱和伽马光谱法进行了分析。通过平衡透析法研究了钆贝酸离子与动物和人类血清白蛋白的结合。... 静脉注射后，钆贝酸二甲基葡胺分布到血浆和细胞外液以及肝细胞内空间。钆贝酸离子通过肾脏和胆汁排泄从血浆中清除。它不会在特定组织中积累，除了在其消除途径相关的组织中暂时积累。钆贝酸离子不会被代谢。它与血浆蛋白的结合太弱，无法通过平衡透析法检测到。...

... The pharmacokinetics were evaluated in rats, rabbits, dogs and monkeys after iv injections of non-labelled gadobenate dimeglumine and, for biodistribution studies, (153)-Gd-labelled gadobenate dimeglumine. Assays were performed by high performance liquid chromatography, X-ray fluorescence and gamma spectrometry. The binding of gadobenate ion to animal and human serum albumin was studied by equilibrium dialysis. ... After iv injection gadobenate dimeglumine distributes into plasma and extracellular fluid as well as into the intrahepatocytic space. Gadobenate ion is cleared from plasma by renal and biliary excretion. It does not accumulate in specific tissues, except temporarily in tissues related to its elimination. Gadobenate ion is not metabolized. Its binding to plasma proteins is too weak to be detected by equilibrium dialysis. ...

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

钆贝酸根离子主要通过肾脏消除，78%到96%的给药剂量在尿液中回收。钆贝酸根离子的总血浆清除率和肾清除率估计相似，分别从0.093 ± 0.010到0.133 ± 0.270 L/hr/kg和0.082 ± 0.007到0.104 ± 0.039 L/hr/kg。清除率与受肾小球滤过作用的物质的清除率相似。平均消除半衰期范围从1.17 ± 0.26到2.02 ± 0.60小时。给药剂量的很小一部分（0.6%到4%）通过胆道途径消除并在粪便中回收。

Gadobenate ion is eliminated predominately via the kidneys, with 78% to 96% of an administered dose recovered in the urine. Total plasma clearance and renal clearance estimates of gadobenate ion were similar, ranging from 0.093 + or - 0.010 to 0.133 + o r- 0.270 L/hr/kg and 0.082+ or - 0.007 to 0.104 + or - 0.039 L/hr/kg, respectively. The clearance is similar to that of substances that are subject to glomerular filtration. The mean elimination half-life ranged from 1.17+ or - 0.26 to 2.02 + or - 0.60 hours. A small percentage ofthe administered dose (0.6% to 4%) is eliminated via the biliary route and recovered in feces.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

尚不清楚钆喷酸二葡甲胺在人类乳汁中的排泄程度。从大鼠实验中得知，给药剂量的不到0.5%会通过乳汁从母体传给新生儿。

It is not known to what extent gadobenate dimeglumine is excreted in human milk. It is known from rat experiments that less than 0.5% of the administered dose is transferred via milk from mother to neonates.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

钆贝酸根离子具有快速的分布半衰期（报告为平均值±标准差），为0.084±0.012至0.605±0.072小时。中心室的分布体积范围从0.074±0.017至0.158±0.038 L/kg，而通过面积估算的分布体积范围从0.170±0.016至0.282±0.079 L/kg。后者的估算大约相当于人体细胞外平均体液量。体外研究表明，钆贝酸根离子与人类血清蛋白没有显著结合。/钆贝酸根离子/

Gadobenate ion has a rapid distribution half-life (reported as mean + or - SD) of 0.084 + or - 0.012 to 0.605 + or - 0.072 hours. Volume of distribution of the central compartment ranged from 0.074:: 0.017 to 0.158 :: 0.038 L/kg, and estimates of volume of distribution by area ranged from 0.170+ or - 0.016 to 0.282+ or - 0.079 L/kg. These latter estimates are approximately equivalent to the average volume of extracellular body water in man. In vitro studies showed no appreciable binding of gadobenate ion to human serum proteins. /Gadobenate ion/

来源:Hazardous Substances Data Bank (HSDB)

制备方法与用途

钆贝酸可用于制备钆贝葡胺：首先将BOPTA与氧化钆在水溶液中反应生成钆贝酸，随后投入葡甲胺进一步制成。具体步骤如下：

1. 向100 mL容器中依次加入7.7 g BOPTA和4.2 g 三氧化二钆，制备钆贝酸。
2. 加入47 mL注射用水，并加热搅拌至60℃，在此温度下保温反应1.5小时。
3. 分十批等量加入5.77 g葡甲胺。每次加完后取少量样品用pH计监测反应液的pH值。若样品pH<6.9，则继续反应直至pH介于6.9~7.3之间再加入下一批葡甲胺。
4. 加完葡甲胺后，反应液继续加热搅拌1.5小时。
5. 然后加入0.16 g药用炭进行脱色，保持上述温度并搅拌1.5小时。
6. 最后趁热过滤，收集滤液并浓缩，最终得到白色固体14.2 g。