2-[Bis[2-[carboxymethyl-[2-(methylamino)-2-oxoethyl]amino]ethyl]amino]acetic acid;gadolinium;hydrate

• 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-[Bis[2-[carboxymethyl-[2-(methylamino)-2-oxoethyl]amino]ethyl]amino]acetic acid;gadolinium;hydrate
• 英文别名: 2-[bis[2-[carboxymethyl-[2-(methylamino)-2-oxoethyl]amino]ethyl]amino]acetic acid;gadolinium;hydrate
• 化学式: C16H31GdN5O9
• 分子量: 594.69
• InChiKey: UOYVVCVWMMGFHR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -4.19
• 重原子数：
  31
• 可旋转键数：
  16
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.69
• 拓扑面积：
  181
• 氢给体数：
  6
• 氢受体数：
  12

ADMET

代谢

此外，在大鼠体内进行了实验，以阐明莫迪酰胺（NaCa DTPA-BMA）的体内代谢。结果显示尿液中有少量转移螯合形式的NaCa DTPA-BMA。高效液相色谱（HPLC）分析表明，这些代谢物是药物的中锌（Zn）和铜（Cu）形式，是由于内源性锌或铜取代了NaCa DTPA-BMA分子中的钙离子。进一步的高效液相色谱和电感耦合等离子体原子发射光谱（ICP-AES）分析表明，未改变的母药、锌形式和铜形式的比例分别大约为92%，7%和1%。这表明莫迪酰胺钠中的钙离子可以被体内的锌或铜离子取代，但程度很小。

In addition, experiments were done /in rats/ to clarify the in vivo metabolism of gadodiamide (NaCa DTPA-BMA). Results show small quantities of transchelated forms of NaCa DTPA-BMA in urine. HPLC analysis demonstrated these metabolites were the Zn and Cu forms of the drug, resulting from displacement of the Ca ion in the NaCa DTPA-BMA molecule by endogeneous Zn or Cu. Further analyses by HPLC and ICP-AES demonstrate that the unchanged parent drug, the Zn and the Cu forms occur in relative quantities of approximately 92%, 7%, and 1%, respectively. This demonstrates that the Ca ion in caldiamide sodium can be replaced by Zn or Cu ions in vivo, but only to a small extent.

来源:Hazardous Substances Data Bank (HSDB)

代谢

此外，在大鼠体内进行了实验，以阐明莫迪酰胺（NaCa DTPA-BMA）的体内代谢。结果显示尿液中有少量转移螯合形式的NaCa DTPA-BMA。高效液相色谱（HPLC）分析表明，这些代谢物是药物的中锌（Zn）和铜（Cu）形式，是由于内源性锌或铜取代了NaCa DTPA-BMA分子中的钙离子。进一步的高效液相色谱和电感耦合等离子体原子发射光谱（ICP-AES）分析表明，未改变的母药、锌形式和铜形式的相对量分别大约为92%，7%和1%。这表明，体内的钙离子可以被锌或铜离子取代，但程度很小。

In addition, experiments were done /in rats/ to clarify the in vivo metabolism of gadodiamide (NaCa DTPA-BMA). Results show small quantities of transchelated forms of NaCa DTPA-BMA in urine. HPLC analysis demonstrated these metabolites were the Zn and Cu forms of the drug, resulting from displacement of the Ca ion in the NaCa DTPA-BMA molecule by endogeneous Zn or Cu. Further analyses by HPLC and ICP-AES demonstrate that the unchanged parent drug, the Zn and the Cu forms occur in relative quantities of approximately 92%, 7%, and 1%, respectively. This demonstrates that the Ca ion in caldiamide sodium can be replaced by Zn or Cu ions in vivo, but only to a small extent.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

识别和使用：钆喷酸二钠是一种用于MRI的静脉注射对比剂，用于可视化大脑（颅内病变）、脊柱和相关组织的异常血管性病变（或被认为会导致血脑屏障异常的病变）。人类暴露和毒性：总是应该考虑可能出现反应的可能性，包括严重的、威胁生命的、致命的、过敏性或心血管反应或其他特异质反应，特别是在那些已知有临床超敏反应、哮喘病史或其他过敏性呼吸系统疾病的病人中。基于钆的对比剂增加了急性或慢性严重肾功能不全患者以及由于肝肾病综合征或肝脏移植手术期间任何严重程度的急性肾功能不全患者发生肾源性系统性纤维化的风险。在这些患者中，除非诊断信息是必不可少的，而且非对比增强MRI无法获得，否则应避免使用基于钆的对比剂。可能增加NSF风险的因素包括重复使用或高于推荐剂量的基于钆的对比剂，以及暴露时肾功能损害的程度。Omniscan的意外鞘内使用已经发生，并导致惊厥、昏迷、感觉和运动神经缺陷。在1157次钆喷酸二钠增强检查后，测量的血清钙浓度从8.65降至8.33 mg/dL，34名患者出现假性严重低钙血症（<6 mg/dL）。在接受高剂量钆喷酸二钠注射和肾功能不全的60名患者中，36.7%的患者在MRI后立即出现假性严重低钙血症。在216名肾功能不全患者中，钆喷酸二钠注射后平均血清镁水平略有升高，从1.69升至1.77 mEq/L。动物研究：钆喷酸二钠注射显示出极低的急性致死毒性，优于钆喷酸二钠甲葡胺注射或钆特酸甲葡胺注射。与钆喷酸二钠甲葡胺注射相比，钆喷酸二钠注射在麻醉犬中快速静脉注射后对心血管和血流动力学功能的影响较小。与所有已知的静脉注射诊断成像剂一样，钆喷酸二钠注射会在肾脏近端小管细胞产生空泡化，而肾功能没有变化。空泡化程度仅为中等，并且在给药后7天内部分消退。钆喷酸二钠注射通过多种血管内和血管外途径给药时没有产生显著的刺激性。在猴子中，连续28天每天给予钆喷酸二钠对肾脏没有影响。该化合物在猴子中连续28天耐受性良好。在大鼠中，仅在较高剂量下出现显著毒性，特别是在雄性动物中，毒性模式（涉及胃、睾丸和皮肤）表明锌代谢紊乱。在兔子的研究中，钆喷酸二钠在5倍于最大推荐人类剂量的剂量下增加了后代骨骼和内脏异常的发生率。钆喷酸二钠在兔子中对胚胎-胎儿发育的负面影响表现为在妊娠期间（大约为最大人类累积剂量的2倍）给药13天后，蜷缩附肢和骨骼畸形的发病率增加。骨骼畸形可能是由母体毒性引起的，因为在妊娠期间给予钆喷酸二钠后，母体的体重显著减轻。以下遗传毒性试验结果为阴性：细菌反向突变试验、CHO/HGPRT正向突变试验、CHO染色体畸变试验和体内小鼠微核试验。

IDENTIFICATION AND USE: Gadodiamide is a contrast agent for intravenous use in MRI to visualize lesions with abnormal vascularity (or those thought to cause abnormalities in the blood-brain barrier) in the brain (intracranial lesions), spine, and associated tissues. HUMAN EXPOSURE AND TOXICITY: The possibility of a reaction, including serious, life threatening, fatal, anaphylactoid or cardiovascular reactions or other idiosyncratic reactions should always be considered especially in those patients with a known clinical hypersensitivity, a history of asthma, or other allergic respiratory disorders. Gadolinium-based contrast agents increase the risk for nephrogenic systemic fibrosis (NSF) in patients with acute or chronic severe renal insufficiency and in patients with acute renal insufficiency of any severity due to the hepato-renal syndrome or in the perioperative liver transplantation period. In these patients, avoid use of gadolinium-based contrast agents unless the diagnostic information is essential and not available with non-contrast enhanced MRI. Among the factors that may increase the risk for NSF are repeated or higher than recommended doses of a gadolinium-based contrast agent and the degree of renal function impairment at the time of exposure. Inadvertent intrathecal use of Omniscan has occurred and caused convulsions, coma, sensory and motor neurologic deficits. Following 1157 gadodiamide-enhanced examinations, measured serum calcium spuriously dropped from 8.65 to 8.33 mg/dL and 34 patients had spurious critical hypocalcemia (<6 mg/dL). Of 60 patients with high-dose gadodiamide injection and renal insufficiency, 36.7% had spurious critical hypocalcemia immediately post MRI. In 216 patients with renal insufficiency, the mean serum magnesium level increased slightly from 1.69 to 1.77 mEq/L following gadodiamide injection. ANIMAL STUDIES: Gadodiamide injection has been shown to have a remarkably low acute lethal toxicity, superior to that of gadopentetate dimeglumine injection or gadoterate meglumine. In comparison with gadopentetate dimeglumine injection, gadodiamide injection had fewer effects on cardiovascular and hemodynamic function after rapid iv injection in anesthetized dogs. Similar to all known iv administered diagnostic imaging agents, gadodiamide injection produces vacuolization of the proximal tubular cells in the kidney, without any change in renal function. The vacuolization was only moderate in degree and was shown to have regressed partially during the 7 days after administration. Gadodiamide injection produced no significant irritation when administered by a variety of intravascular and extravascular routes. In monkeys, administration of gadodiamide daily for 28 days had no effect on the kidney . The compound was well tolerated in monkeys for 28 consecutive days. In rats, significant toxicity occurred only at high doses, particularly in male animals, and the pattern of toxicity (involving the stomach, testes, and skin) suggested a disturbance of zinc metabolism. Studies in rabbits showed that gadodiamide at doses 5 times the maximum recommended human dose increased the incidence of skeletal and visceral abnormalities in the offspring. Gadodiamide has been shown to have an adverse effect on embryo-fetal development in rabbits that is observed as an increased incidence of flexed appendages and skeletal malformations administered for 13 days during gestation (approximately 2 times the maximum human cumulative dose) . Skeletal malformations may be due to maternal toxicity since the body weight of the dams was significantly reduced in response to gadodiamide administration during pregnancy. The results of the following genotoxicity assays were negative: bacterial reverse mutation assay, CHO/HGPRT forward mutation assay, CHO chromosome aberration assay, and the in vivo mouse micronucleus assay.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

在大鼠接受顺铂（1毫克/千克）每周一次腹腔注射（ip）共10周后，通过静脉注射（iv）高剂量的盐水、泛影葡胺、碘克酸、钆喷酸葡胺和钆双胺（剂量为4.59毫摩尔/千克体重）监测24天内的尿液和血清指标。每组有10只大鼠。光镜和电镜检查显示，顺铂诱导了严重的形态学变化，包括管状扩张、萎缩和坏死，然而，对比剂并未引起任何额外的形态学变化。在顺铂肾病变中，钆喷酸葡胺、泛影葡胺和碘克酸显著增加了（3-20倍）与静脉注射盐水相比的白蛋白尿，而钆双胺则没有。白蛋白尿在泛影葡胺注射后最高。所有四种对比剂都立即并短暂地显著增加了刷状缘酶碱性磷酸酶和γ-谷氨酰转移酶（125-500倍）以及细胞质酶丙氨酸氨基肽酶和乳酸脱氢酶（16-100倍）的排泄。与盐水相比，离子型对比剂显著增加了葡萄糖（两倍）和钠（三到五倍）的排泄，而非离子型对比剂则没有。"作者得出结论，"高剂量的放射学和磁共振对比剂在大鼠顺铂肾病变中引起了暂时性的功能障碍。钆双胺引起的功能障碍最少，泛影葡胺引起的功能障碍最多。

... Urine and serum profiles were monitored for 24 days after iv injections of saline, diatrizoate, iohexol, gadopentetate dimeglumine, and gadodiamide in high doses (4.59 mmol/kg body weight) in rats that received a weekly intraperitoneal (ip) injection of cisplatin (1 mg/kg) for 10 weeks. There were 10 rats in each group. ... Light and electron microscopy showed severe morphologic changes, including tubular dilatation, atrophy, and necrosis induced by cisplatin; however, the contrast media did not induce any additional morphologic changes. Gadopentetate dimeglumine, diatrizoate, and iohexol significantly increased (3-20 times) albuminuria compared with iv saline in cisplatin nephropathy, whereas gadodiamide did not. Albuminuria was highest after diatrizoate injection. All four contrast media caused an immediate and transient significant increase in the excretion of the brush border enzymes alkaline phosphatase and gamma-glutamyltransferase (125-500 times) and the cytoplasmatic enzymes alanine aminopeptidase and lactate dehydrogenase (16-100 times). Compared with saline, the ionic agents significantly increased the excretion of both glucose (two times) and sodium (three to five times), whereas the nonionic agents did not. /The authors concluded that/ high doses of radiologic and magnetic resonance contrast agents cause temporary dysfunction in rats with cisplatin nephropathy. Gadodiamide caused the least dysfunction and diatrizoate the most.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

... /一名54岁女性的病例/，在使用标准比色分析法测量钆喷酸葡胺增强磁共振成像后，她的/误报为“严重低”的血清钙水平被测量出来。在另外2名患者中也观察到了同样的现象... 几个小时后重复测量的血清钙值在正常范围内。商业上可用的基于钆的对比剂可能会在使用标准比色分析法测量时导致严重低血清钙值。医生对钆喷酸葡胺引起的假性低钙血症的认识可能防止不必要的治疗干预。

... /The case of/ a 54-year-old woman in whom a /spuriously/ "critically low" serum calcium level was measured with standard colorimetric assay after gadodiamide-enhanced magnetic resonance imaging /is reported/. The same phenomenon was noted in 2 other patients ... Repeat serum calcium measurements performed several hours later were within normal limits. Commercially available gadolinium-based contrast agents might precipitate critically low serum calcium values when measured by standard colorimetric assay. Physician awareness of gadodiamide-induced spurious hypocalcemia might prevent unnecessary therapeutic interventions.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

一起报告了一位78岁男性在使用标准比色分析法测量下，因在磁共振血管造影中使用钆喷酸葡胺后出现“极度低”血清钙水平的案例。使用吸收光谱学重新分析同一血清样本，结果显示正常的钙值，从而确认了伪低钙血症的诊断。

... A case in which a 78-year-old man had a /spuriously/ "critically low" serum calcium level measured with use of standard colorimetric assay after gadodiamide administration during magnetic resonance angiography /is reported/. Reanalysis of the same serum specimen using absorption spectroscopy revealed normal calcium values, confirming the diagnosis of spurious hypocalcemia.

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，按训练进行操作。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，让患者向前倾或将其置于左侧（如果可能的话，头部向下），以保持呼吸道畅通，防止窒息。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)

吸收、分配和排泄

本研究的目标是确定在给患者标准临床剂量两种基于钆的造影剂（ProHance和Omniscan）后，人类骨骼组织中剩余的钆（Gd）浓度。在给接受髋关节置换手术的患者注射0.1毫摩尔/公斤的钆螯合物后，收集骨骼标本并进行分析，并与没有钆螯合物给药历史的同龄对照组进行比较。骨骼标本在新鲜、冷藏后冷冻保存。在研磨和冷冻干燥后，使用特氟龙炸弹和浓缩硝酸进行组织消化。使用电感耦合等离子体质谱（ICP-MS）开发并验证了一种分析骨骼标本中钆的方法。结果与之前使用不同技术分析相同组织标本的研究进行了比较。ICP-MS测量的Omniscan在骨骼中的组织保留为1.77+/-0.704微克Gd/克骨（n=9），ProHance为0.477+/-0.271微克Gd/克骨（n=10）。这些发现证实了之前ICP-AES研究的成果。Omniscan（Gd[DTPA-BMA]）在骨骼中留下的钆大约是ProHance（Gd[HP-DO3A]）的4倍（之前的研究为2.5倍）。

The objective of this study was to determine the gadolinium (Gd) concentration remaining in human bone tissue after administration of standard clinical doses of 2 Gd-based contrast agents: ProHance and Omniscan. After administration of 0.1 mmol/kg of Gd chelate to patients undergoing hip replacement surgery, bone specimens were collected and analyzed, and compared with an age-matched control population without a history of Gd chelate administration. Bone specimens were collected fresh, refrigerated, and subsequently frozen. After grinding and freeze-drying, tissue digestion was performed using Teflon bombs and concentrated nitric acid. A method for analysis of Gd in bone specimens was developed and validated using inductively coupled plasma mass spectroscopy (ICP-MS). Results were compared with a previous study using a different technique for analysis of the same tissue specimens. Tissue retention was 1.77+/-0.704 microg Gd/g bone (n=9) for Omniscan and 0.477+/-0.271 microg Gd/g bone (n=10) for ProHance measured by ICP-MS. These findings confirmed results from the previous ICP-AES study. Omniscan (Gd[DTPA-BMA]) left approximately 4 times (previous study 2.5 times) more Gd behind in bone than did ProHance (Gd[HP-DO3A]).

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

二十七名患者——九名肾功能严重减退（肾小球滤过率，2-10 mL/min），九名接受血液透析，九名接受持续非卧床腹膜透析——在接受了钆喷酸葡胺注射（每公斤体重0.1毫摩尔）后，分别随访了5天、8天和22天。钆喷酸葡胺注射没有改变肾功能。在肾功能严重减退的患者中，钆喷酸葡胺注射的消除半衰期延长（34.3小时±22.9），与健康志愿者数据（1.3小时±0.25）相比。在一次血液透析过程中，平均有65%的钆喷酸葡胺被消除。在持续非卧床腹膜透析22天后，总钆喷酸葡胺量的69%被排出；这反映了低的腹膜清除率。在所有患者中，没有发现钆喷酸葡胺的代谢或金属转移现象。...

Twenty-seven patients--nine with severely reduced renal function (glomerular filtration rate, 2-10 mL/min), nine undergoing hemodialysis, and nine undergoing continuous ambulatory peritoneal dialysis--were followed up for 5, 8, and 22 days, respectively, after receiving gadodiamide injection (0.1 mmol per kilogram body weight). Gadodiamide injection caused no changes in renal function. In patients with severely reduced renal function, the elimination half-life of gadodiamide injection was prolonged (34.3 hours +/- 22.9) compared with data in healthy volunteers (1.3 hours +/- 0.25). An average of 65% of the gadodiamide injected was eliminated during a hemodialysis session. After 22 days of continuous ambulatory peritoneal dialysis, 69% of the total amount of gadodiamide was excreted; this reflects the low peritoneal clearance. In all patients, no metabolism or transmetallation of gadodiamide was found. ...

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

钆喷酸葡胺的药代动力学行为与其细胞外分布一致。钆喷酸葡胺被证明可以快速排泄，主要通过肾脏。在大鼠中，给药剂量的大约94%在给药后第一个24小时内通过尿液排出。在同一时期内，大约有1%到4%出现在粪便中。

The pharmacokinetic behavior of gadodiamide was consistent with its extracellular distribution. ... Gadodiamide was shown to be excreted rapidly, primarily through the kidneys. In rats, 94% of the administered dose was excreted in the urine within the first 24 hours after administration. Approximately 1% to 4% appeared in the feces during the same period.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在大鼠中，静脉注射给予钆喷酸葡胺（NaCa DTPA-BMA）（0.015 mmol/kg）的（14）C标记形式后，药物的血浆浓度迅速下降，消除半衰期为0.31小时，分布体积为244 mL/kg，血浆清除率为9.2 mL/min/kg。这些结果表明NaCa DTPA-BMA分布到细胞外液区间，并通过肾小球滤过作用从肾脏排泄。给予的放射性剂量中，86.6%在注射后4小时内通过尿液排出，120小时内在尿液中共排出95.3%，在粪便中排出3.3%。

... /In rats/ following iv dosing of gadodiamide (NaCa DTPA-BMA) (0.015 mmol/kg) in a (14)C-labeled form, plasma concentrations of the drug declined rapidly with an elimination half-live of 0.31 hr, a distribution volume of 244 mL/kg and a plasma clearance of 9.2 mL/min/kg. These results demonstrate that NaCa DTPA-BMA distributes into the extracellular fluid compartment and is renally excreted via glomerular filtration. Of the dose of radioactivity given, 86.6% was excreted in urine by 4 hr after injection, and 95.3% in urine and 3.3% in feces by 120 hr. ...

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

这项研究的目标是确定在给患者标准临床剂量两种基于钆的造影剂（ProHance和Omniscan）后，人类骨骼组织中剩余的钆（Gd）浓度。在给接受髋关节置换手术的患者注射0.1毫摩尔/公斤的钆螯合物后，收集骨骼标本并进行分析，并与没有钆螯合物给药历史的同龄对照组进行比较。骨骼标本在新鲜、冷藏后冷冻保存。在研磨和冷冻干燥后，使用特氟龙炸弹和浓缩硝酸进行组织消化。开发并验证了一种用于分析骨骼标本中钆的方法，使用电感耦合等离子体质谱（ICP-MS）。结果与之前使用不同技术分析相同组织标本的研究进行了比较。通过ICP-MS测量，Omniscan的组织的保留量为1.77+/-0.704微克钆/克骨（n=9），ProHance的保留量为0.477+/-0.271微克钆/克骨（n=10）。这些发现证实了之前ICP-AES研究的成果。Omniscan（Gd[DTPA-BMA]）在骨骼中留下的钆大约是ProHance（Gd[HP-DO3A]）的4倍（之前的研究是2.5倍）。

The objective of this study was to determine the gadolinium (Gd) concentration remaining in human bone tissue after administration of standard clinical doses of 2 Gd-based contrast agents: ProHance and Omniscan. After administration of 0.1 mmol/kg of Gd chelate to patients undergoing hip replacement surgery, bone specimens were collected and analyzed, and compared with an age-matched control population without a history of Gd chelate administration. Bone specimens were collected fresh, refrigerated, and subsequently frozen. After grinding and freeze-drying, tissue digestion was performed using Teflon bombs and concentrated nitric acid. A method for analysis of Gd in bone specimens was developed and validated using inductively coupled plasma mass spectroscopy (ICP-MS). Results were compared with a previous study using a different technique for analysis of the same tissue specimens. Tissue retention was 1.77+/-0.704 microg Gd/g bone (n=9) for Omniscan and 0.477+/-0.271 microg Gd/g bone (n=10) for ProHance measured by ICP-MS. These findings confirmed results from the previous ICP-AES study. Omniscan (Gd[DTPA-BMA]) left approximately 4 times (previous study 2.5 times) more Gd behind in bone than did ProHance (Gd[HP-DO3A]).

来源:Hazardous Substances Data Bank (HSDB)