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: 原料药 - 诊断用药
• 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