多它灵

• 物质功能分类: 原料药 - 诊断用药 - 影象检查用药
• 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
• 中文名称: 多它灵
• 英文名称: gadoteric dcid meglumine
• 英文别名: gadoterate meglumine；gadolinium(3+);methyl-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]azanium;2-[4,7,10-tris(carboxylatomethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetate
• 化学式: C₇H₁₇NO₅*C₁₆H₂₅N₄O₈*Gd
• 分子量: 753.862
• InChiKey: RYHQMKVRYNEBNJ-BMWGJIJESA-K

计算性质

• 辛醇/水分配系数(LogP)：
  -9.82
• 重原子数：
  42
• 可旋转键数：
  11
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.83
• 拓扑面积：
  284
• 氢给体数：
  7
• 氢受体数：
  18

ADMET

代谢

钆特酸尚未知是否被代谢。

Gadoterate is not known to be metabolized.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

识别：钆特酸葡甲胺是一种用于磁共振成像的顺磁性大环离子对比剂。人类暴露和毒性：最常见报告的不良反应是头痛（1.5%）。在接受DOTAREM治疗的患者中，发生率小于0.2%的不良反应包括：感觉寒冷、皮疹、嗜睡、疲劳、头晕、呕吐、瘙痒、感觉异常、味觉障碍、肢体疼痛、焦虑、高血压、心悸、咽部不适、血清肌酐升高和注射部位反应，包括部位炎症、外渗、瘙痒和温暖感。钆基对比剂（GBCAs）会增加药物消除受损患者的肾源性系统性纤维化（NSF）风险。除非诊断信息是必需的，且无法通过无对比剂MRI或其他方式获得，否则应避免在这些患者中使用GBCAs。NSF可能导致影响皮肤、肌肉和内脏器官的致命或致残性纤维化。NSF风险最高的患者包括：慢性严重肾病患者（GFR < 30 mL/min/1.73 m²）或急性肾损伤患者。筛查患者的急性肾损伤和其他可能降低肾功能的情况。对于慢性肾功能降低风险的患者（例如年龄> 60岁、高血压、糖尿病），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DOTAREM剂量，并在再次给药前留出足够的时间以从体内消除药物。 动物研究：在大鼠和家兔中进行了钆特酸葡甲胺的生殖和发育毒性研究。钆特酸葡甲胺以0、2、4和10 mmol/kg/天的剂量（或基于体表面积的3.2、6.5和16.2倍推荐人类剂量）静脉注射给雌性大鼠，在配种前14天开始，整个配种期直至妊娠第17天。以0、1、3和7 mmol/kg/天的剂量（或基于体表面积的3.3、10和23倍人类剂量）静脉注射给妊娠的家兔，从GD6至GD19。在大鼠或家兔中，直到大鼠10 mmol/kg/天或家兔3 mmol/kg/天的剂量，未观察到对胚胎胎儿发育的影响。在大鼠10 mmol/kg/天（或基于体表面积的16倍人类剂量）和家兔7 mmol/kg/天（基于体表面积的23倍人类剂量）时观察到母体毒性。

IDENTIFICATION: Gadoterate meglumine is a paramagnetic macrocyclic ionic contrast agent administered for magnetic resonance imaging. HUMAN EXPOSURE AND TOXICITY: The most frequently reported adverse reaction was headache (1.5%) Adverse reactions that occurred with a frequency < 0.2% in patients who received DOTAREM include: feeling cold, rash, somnolence, fatigue, dizziness, vomiting, pruritus, paresthesia, dysgeusia, pain in extremity, anxiety, hypertension, palpitations, oropharyngeal discomfort, serum creatinine increased and injection site reactions, including site inflammation, extravasation, pruritus, and warmth. 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 fibrosis affecting the skin, muscle and internal organs. The risk for NSF appears highest among patients with: Chronic, severe kidney disease (GFR < 30 mL/min/1.73 m2), 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 (e.g. age > 60 years, hypertension, diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing. For patients at highest risk for NSF, do not exceed the recommended DOTAREM dose and allow a sufficient period of time for elimination of the drug from the body prior to any re-administration. Animals Studies: Reproductive and developmental toxicity studies were conducted with gadoterate meglumine in rats and rabbits. Gadoterate meglumine was administered intravenously in doses of 0, 2, 4 and 10 mmol/kg/day (or 3.2, 6.5 and 16.2 times the recommended human dose based on body surface area) to female rats for 14 days before mating throughout the mating period and until gestation day (GD) 17. Pregnant rabbits were intravenously administered gadoterate meglumine at the dose levels of 0, 1, 3 and 7 mmol/kg/day (or 3.3, 10 and 23 times the human doses based on body surface area) from GD6 to GD19. No effects on embryo fetal development were observed in rats or rabbits at doses up to 10 mmol/kg/day in rats or 3 mmol/kg/day in rabbits. Maternal toxicity was observed in rats at 10 mmol/kg/day (or 16 times the human dose based on body surface area) and in rabbits at 7 mmol/kg/day (23 times the human dose based on body surface area).

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

Gadoterate是一种顺磁性分子，当置于磁场中时会产生磁矩。这个磁矩增强了其周围水分子的质子弛豫速率，导致组织信号强度（亮度）的增加。

Gadoterate is a paramagnetic molecule that develops a magnetic moment when placed in a magnetic field. The magnetic moment enhances the relaxation rates of water protons in its vicinity, leading to an increase in signal intensity (brightness) of tissues.

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和。如果患者停止呼吸，请开始人工呼吸，最好使用需求阀复苏器、球囊阀面罩设备或口袋面罩，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。如果患者呕吐，让患者身体前倾或将其置于左侧（如果可能，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。寻求医疗救助。 /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。使用气囊面罩装置的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D5W TKO /SRP: "保持开放"，最低流量/。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

在给予0.1 mmol/kg剂量的DOTAREM后，总钆主要通过尿液排泄，女性和男性受试者分别有72.9 +/- 17.0 % 和 85.4 +/- 9.7 % 在48小时内被消除（平均值 +/- 标准差）。在累计剂量达到0.3 mmol/kg（0.1 + 0.2 mmol/kg，20分钟后），女性和男性受试者的尿液中分别有85.5 +/- 13.2 % 和 92.0 +/- 12.0 % 在48小时内被回收。在健康受试者中，总钆的肾清除率和总清除率相似（女性分别为1.27 +/- 0.32和1.74 +/- 0.12 mL/min/kg；男性分别为1.40 +/- 0.31和1.64 +/- 0.35 mL/min/kg），这表明该药物主要通过肾脏清除。在研究的剂量范围内（0.1至0.3 mmol/kg），总钆的动力学表现似乎呈线性。

Following a 0.1 mmol/kg dose of DOTAREM, total gadolinium is excreted primarily in the urine with 72.9 +/- 17.0 % and 85.4 +/- 9.7 % (mean +/- SD) eliminated within 48 hours, in female and male subjects, respectively. Similar values were achieved after a cumulative dose of 0.3 mmol/kg (0.1 + 0.2 mmol/kg, 20 minutes later), with 85.5 +/- 13.2 % and 92.0 +/- 12.0 % recovered in urine within 48 hrs in female and male subjects respectively. In healthy subjects, the renal and total clearance rates of total gadolinium are comparable (1.27 +/- 0.32 and 1.74 +/- 0.12 mL/min/kg in females; and 1.40 +/- 0.31 and 1.64 +/- 0.35 mL/min/kg in males, respectively) indicating that the drug is primarily cleared through the kidneys. Within the studied dose range (0.1 to 0.3 mmol/kg), the kinetics of total gadolinium appear to be linear.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

正常受试者稳态下总钆的分布体积分别为女性179 +/- 26 毫升/千克，男性211 +/- 35 毫升/千克，大致相当于细胞外液的含量。

The volume of distribution at steady state of total gadolinium in normal subjects is 179 +/- 26 and 211 +/- 35 mL/kg in female and male subjects respectively, roughly equivalent to that of extracellular water.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

钆特酸不通过完整的血脑屏障，因此不会增强具有正常血脑屏障的正常大脑或病变，例如囊肿、成熟的术后疤痕。然而，血脑屏障的破坏或异常血管化允许钆特酸在诸如肿瘤、脓肿和梗死等病变中分布。

Gadoterate does not cross the intact blood-brain barrier and, therefore, does not enhance normal brain or lesions that have a normal blood-brain barrier, e.g. cysts, mature post-operative scars. However, disruption of the blood-brain barrier or abnormal vascularity allows distribution of gadoterate in lesions such as neoplasms, abscesses, and infarcts.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

尚不清楚DOTAREM是否会在人类乳汁中排泄。有限的案例报告显示，在哺乳期母亲中使用GBCAs（钆基对比剂）时，大约有0.01%到0.04%的母体钆剂量会通过乳汁排泄。由于许多药物都会通过人类乳汁排泄，当给哺乳期妇女使用DOTAREM时，应谨慎。非临床数据显示，钆特酸葡甲胺以非常小的量（小于静脉给药剂量的0.1%）排泄到乳汁中，并且通过胃肠道的吸收不良。

It is not known whether DOTAREM is excreted in human milk. Limited case reports on use of GBCAs in nursing mothers indicate that 0.01 to 0.04% of the maternal gadolinium dose is excreted in human breast milk. Because many drugs are excreted in human milk, exercise caution when DOTAREM is administered to a nursing woman. Nonclinical data show that gadoterate meglumine is excreted into breast milk in very small amounts (< 0.1% of the dose intravenously administered) and the absorption via the gastrointestinal tract is poor.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为产物：
  描述：

  钆特酸 、 N-甲基-D-葡胺 以 水 为溶剂， 反应 0.33h， 以98.32%的产率得到多它灵
  参考文献：
  名称：

  KR20210152656A

  摘要：

  公开号：

文献信息

• 一种制备造影剂方法
  申请人：江苏恒瑞医药股份有限公司

  公开号：CN111375071B

  公开（公告）日：2023-04-07

  本发明提供一种制备造影剂的方法。具体而言，本发明将含有大环螯合物与镧系元素的络合物液体组合物依次经Relite CNS阳离子树脂、Relite 3As阴离子树脂获得高纯度液体溶液，随后调节溶液pH值，再经冷冻干燥或低温喷雾干燥获得造影剂固体，进一步称取定量固体配制成造影剂配制品，供医学上造影使用。
• [EN] NOVEL MANUFACTURING PROCESS FOR GADOLINIUM COMPLEXES<br/>[FR] NOUVEAU PROCÉDÉ DE FABRICATION DE COMPLEXES DE GADOLINIUM
  申请人：GE HEALTHCARE AS

  公开号：WO2021123383A1

  公开（公告）日：2021-06-24

  The present invention provides a novel method for removal of gadolinium ions from a solution comprising gadolinium complexed with DOTA. The method of the invention is relatively straightforward and cost-efficient compared with known methods.

  本发明提供了一种新颖的方法，用于从含有与DOTA络合的钆离子的溶液中去除钆离子。与已知方法相比，本发明的方法相对简单且成本效益较高。
• 一种1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸的制备方法
  申请人：江苏恒瑞医药股份有限公司

  公开号：CN108658882A

  公开（公告）日：2018-10-16

  本发明涉及一种1,4,7,10‑四氮杂环十二烷‑1,4,7,10‑四乙酸的制备方法。具体而言，该方法选用重结晶方式获得高纯度式I化合物，进一步地，将葡甲胺、Gd2O3与式I化合物络合即可得钆特酸葡甲胺，所述方法操作简便，成本低，绿色环保，适合于大规模生产。
• NANOMATERIAL AND METHOD OF PRODUCTION OF A NANOMATERIAL FOR MEDICAL APPLICATIONS, SUCH AS MRI OR SERS
  申请人：UNIVERSITE PARIS NORD

  公开号：EP3354375A1

  公开（公告）日：2018-08-01

  A method for producing nanomaterial product which comprises at least one nanoparticle Gold-metal-Polymer, the polymer comprising at least one biopolymer, the atoms of metal being linked with the atom of Gold, the metal being chosen among: Gd, Co, Eu, Tb, Ce, Mn, Fe, Zn, Ag, the method being realized in an aqueous solvent, without reactive or stabilizer agent, and presenting a step of reducing: tetrachloroauric acid (HAuCl4) and metal ions, in the presence of the biopolymer, the biopolymer being used as a stabilizer agent.

  一种生产纳米材料产品的方法，该纳米材料产品包括至少一种纳米颗粒金-金属-聚合物，该聚合物包括至少一种生物聚合物，金属原子与金原子相连，金属选自以下金属：Gd、Co、Eu、Tb、Ce、Mn、Fe、Zn、Ag：该方法在水性溶剂中实现，不含反应剂或稳定剂，在生物聚合物存在的情况下，还原步骤包括：四氯金酸（HAuCl4）和金属离子，生物聚合物用作稳定剂。
• [EN] NANOMATERIAL AND METHOD OF PRODUCTION OF A NANOMATERIAL FOR MEDICAL APPLICATIONS, SUCH AS MRI OR SERS<br/>[FR] NANOMATÉRIAU ET PROCÉDÉ DE PRODUCTION D'UN NANOMATÉRIAU POUR DES APPLICATIONS MÉDICALES, TELLES QUE L'IRM OU LA DRES
  申请人：UNIV PARIS NORD

  公开号：WO2018138280A1

  公开（公告）日：2018-08-02

  A method for producing nanomaterial product which comprises at least one hybrid nanoparticle Gold-metal-Polymer, the polymer comprising at least one biopolymer, the atoms of metal being linked with the atom of Gold, the metal being chosen among: Gd, Co, Eu, Tb, Ce, Mn, Fe, Zn, Cu, the method being realized in an aqueous solvent, without reactive or stabilizer agent, and presenting a step of reducing: tetrachloroauric acid (HAuCl4) and metal ions, in the presence of the biopolymer, the biopolymer being used as a stabilizer agent.