Gadolinium-DO3A-butriol | 138071-82-6

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 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: Gadolinium-DO3A-butriol
• 英文别名: 2-[4,10-bis(carboxylatomethyl)-7-[(2S,3R)-1,3,4-trihydroxybutan-2-yl]-1,4,7,10-tetrazacyclododec-1-yl]acetate;gadolinium(3+)
• CAS: 138071-82-6；770691-21-9
• 化学式: C18H31GdN4O9
• 分子量: 604.7
• InChiKey: ZPDFIIGFYAHNSK-YYLIZZNMSA-K

物化性质

• 熔点：
  >264°C (dec.)
• 密度：
  1.3 g/mL at 37 °C
• 溶解度：
  可微溶于水
• 物理描述：
  Solid
• 粘度：
  4.96 mPa.s at 37 °C

计算性质

• 辛醇/水分配系数(LogP)：
  -7.83
• 重原子数：
  32
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.83
• 拓扑面积：
  194
• 氢给体数：
  3
• 氢受体数：
  13

ADMET

代谢

钆喷酸葡胺不进行代谢。

Gadobutrol is not metabolized.

来源:DrugBank

毒理性

• 毒性总结

在给予20毫摩尔/公斤单次静脉给药后，观察到啮齿类动物的致死性。这代表了一个至少比人类标准单次诊断剂量（0.1毫摩尔/公斤）高2个数量级的剂量。尚未进行致癌性研究。在体外逆转突变试验中，使用细菌或中国仓鼠V79细胞的HGPRT（次黄嘌呤-鸟嘌呤磷酸核糖基转移酶）试验中，未观察到突变。同样，在人类外周血淋巴细胞的染色体畸变试验中也没有看到突变。在小鼠接受0.5毫摩尔/公斤静脉注射后的体内微核试验中，结果也为阴性。基于身体表面积，给予雄性和雌性大鼠相当于人类剂量12.2倍的剂量，未观察到对生育或生殖能力的损害。在兔子上进行静脉外给药后，观察到局部对注射部位的耐受性反应，并伴有炎症细胞的浸润，这表明如果对比剂在临床环境中泄漏到静脉周围，可能会引起局部刺激。

Lethality was observed in rodents after a single intravenous administration of 20 mmol/kg. This represents a dose of at least 2 orders of magnitude higher than the standard single diagnostic dose in humans (0.1 mmol/kg). No carcinogenicity studies have been conducted. No mutagenesis was observed in vitro in reverse mutation tests in bacteria, or in the HGPRT (hypoxanthine-guanine phosphoribosyl transferase) test using Chinese hamster V79 cells. Similarly, no mutagenesis was seen in chromosome abberation tests of human peripheral blood lymphocytes. It was also negative in in-vivo micronucleus tests in mice following a 0.5mmol/kg intravenous injection. No fertility or reproductive impairment was observed in male and female rates given doses 12.2 times human equivalent doses, based on body surface area. Intolerance reactions local to the injection site have been observed in rabbits after paravenous administration, and are associated with the infiltration of inflammatory cells, suggesting the possibility of local irritation if the contrast medium leaks around veins in a clinical setting.

来源:DrugBank

毒理性

• 毒性总结

识别：钆贝特罗用于成人及儿科患者（包括足月新生儿）的磁共振成像（MRI）中，用于检测和可视化中枢神经系统破坏的血脑屏障（BBB）区域和/或异常血管情况，并用于MRI评估恶性乳腺疾病的存情况和范围。人类暴露和毒性：在给予钆维斯特后，罕见地发生了从轻度到严重，甚至包括死亡在内的心血管、呼吸或皮肤表现的花粉症和其他超敏反应。在给予钆维斯特之前，需评估所有患者是否有对比剂、支气管哮喘和/或过敏性疾病的历史。这些患者可能存在对钆维斯特超敏反应的增力风险。仅在能够迅速提供治疗超敏反应的人员和疗法的情况下，包括接受复苏训练的人员，才可给予钆维斯特。大多数对钆维斯特的超敏反应发生在给药后半小时内。延迟反应可能在给药后数天内发生。动物研究：在大鼠哺乳研究中，钆贝特罗在乳汁中的含量低于静脉给药剂量的0.1%，且胃肠道吸收不良（口服给药剂量的约5%通过尿液排出）。在接受0.5 mmol/kg静脉注射[153Gd]-钆贝特罗的哺乳大鼠中，给药后3小时内，总给药放射性活性的0.01%通过母奶转移给了幼崽。在给予母体毒性剂量钆贝特罗的怀孕大鼠（= 7.5 mmol/kg体重；基于体表面积相当于人类剂量的12倍）和怀孕家兔（= 2.5 mmol/kg体重；基于体表面积相当于推荐人类剂量的8倍）中，也发生了胚胎致死和胚胎发育迟缓。在家兔中，这一发现发生在没有明显母体毒性证据且胎盘转移最小的情况下（胎崽中检测到的给药剂量的0.01%）。

IDENTIFICATION: Gadobutrol is indicated for use with magnetic resonance imaging (MRI) in adult and pediatric patients (including term neonates) to detect and visualize areas with disrupted blood brain barrier (BBB) and/or abnormal vascularity of the central nervous system and for use with MRI to assess the presence and extent of malignant breast disease. HUMAN EXPOSURE AND TOXICITY: Anaphylactic and other hypersensitivity reactions with cardiovascular, respiratory or cutaneous manifestations, ranging from mild to severe, including death, have uncommonly occurred following Gadavist administration. Before Gadavist administration, assess all patients for any history of a reaction to contrast media, bronchial asthma and/or allergic disorders. These patients may have an increased risk for a hypersensitivity reaction to Gadavist. Administer Gadavist only in situations where trained personnel and therapies are promptly available for the treatment of hypersensitivity reactions, including personnel trained in resuscitation. Most hypersensitivity reactions to Gadavist have occurred within half an hour after administration. Delayed reactions can occur up to several days after administration. ANIMAL STUDIES: In rat lactation studies, gadobutrol was present in milk in amounts less than 0.1% of the dose intravenously administered and the gastrointestinal absorption is poor (approximately 5% of the dose orally administered was excreted in the urine). In lactating rats receiving 0.5 mmol/kg of intravenous [153Gd]-gadobutrol, 0.01% of the total administered radioactivity was transferred to the pup via maternal milk, within 3 hours after administration. Embryolethality and retardation of embryonal development also occurred in pregnant rats receiving maternally toxic doses of gadobutrol (= 7.5 mmol/kg body weight; equivalent to12 times the human dose based on body surface area) and in pregnant rabbits (= 2.5 mmol/kg body weight; equivalent to 8 times the recommended human dose based on body surface area). In rabbits, this finding occurred without evidence of pronounced maternal toxicity and with minimal placental transfer (0.01% of the administered dose detected in the fetuses).

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、气囊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，防止吸入性肺炎。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，协助通气。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……。预期癫痫发作，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）连续冲洗每只眼睛……。不要使用催吐剂。对于摄入，如果患者能够吞咽、有强烈的咳嗽反射且不流口水，则用水冲洗口腔，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……。/毒物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受体激动剂，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%葡萄糖溶液（D5W），保持通路开放，最低流量/ 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……。使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

• 吸收

具有正常肾功能时，AUC为1.1 ± 0.1 毫摩尔·小时/升。

With normal renal function, the AUC is 1.1 ± 0.1 mmol·h/L.

来源:DrugBank

吸收、分配和排泄

• 消除途径

通过肾脏的肾小球过滤而未发生改变地排出。肾外消除可以忽略不计。

Excreted unchanged via glomerular filtration by the kidneys. Extrarenal elimination is negligible.

来源:DrugBank

吸收、分配和排泄

• 分布容积

静脉给药后迅速分布到细胞外空间。在给予0.1毫摩尔/千克体重的剂量后，注射后2分钟测得的平均血浆水平为0.59毫摩尔/升，注射后60分钟为0.3毫摩尔/升。

Rapid distribution to extracellular space occurs after intravenous administration. After a dose of 0.1mmol/kg body weight, an average plasma level of 0.59 mmol/L was measured 2 minutes post injection, and 0.3mmol/L 60 minutes post injection.

来源:DrugBank

吸收、分配和排泄

• 清除

在健康受试者中，肾清除率为1.1 - 1.7 mL/(min·kg)。静脉注射后2小时内，超过50%通过尿液排出。在12小时内，超过90%的给药剂量被排出。在使用0.1mmol/kg剂量的老年受试者中，观察到清除率略有降低。基于130名2-17岁的儿科受试者的群体药代动力学分析，2至17岁年龄范围内儿童的中位AUC、清除率和消除半衰期相似。在2-6岁的儿童（n=45）中，钆布醇的中位AUC为0.8 mmol·h/L，中位清除率为0.13 L/hr/kg，中位消除半衰期为1.75小时。在7-11岁的儿童（n=39）中，钆布醇的中位AUC为1.0 mmol·h/L，中位清除率为0.1 L/hr/kg，中位消除半衰期为1.61小时。在12-17岁的儿童（n=46）中，钆布醇的中位AUC为1.2 mmol·h/L，中位清除率为0.09 L/hr/kg，中位消除半衰期为1.65小时。大约99%（中位数）的剂量在6小时后通过尿液回收。钆布醇的血清半衰期延长与肌酐清除率降低相关。在轻中度肾功能损害的患者（80>CLCR>30 mL/min）中，消除半衰期为5.8 ± 2.4小时，AUC为4.0 ± 1.8 mmol·h/L，72小时内完全通过尿液回收。在重度肾功能损害的患者（CLCR<30 mL/min）中，消除半衰期为17.6 ± 6.2小时，AUC为11.5 ± 4.3 mmol·h/L，5天内完全通过尿液回收。医师可以考虑在已经接受血液透析的患者中，在钆布醇给药后立即开始血液透析以帮助消除。一次透析会议后，初始剂量的68%被移除，第二次会议后为94%，第三次会议后为98%。

In healthy subjects, renal clearance is 1.1 - 1.7mL/(min·kg). Within 2 hours of intravenous injection more than 50% is eliminated via the urine. Within 12 hours more than 90% of the given dose is eliminated. Clearance was observed to be slightly lower in elderly subjects, when using a 0.1mmol/kg dose. In the pediatric population, the median AUC, clearance and elimination half life was observed to be similar across the age range of 2-17, based on a population pharmacokinetic analysis of 130 pediatric subjects aged 2-17. In children aged 2-6 (n=45) the median AUC of gadobutrol was 0.8 mmol·h/L, the median clearance was 0.13L/hr/kg, and the median elimination half life was 1.75h. In children aged 7-11 (n=39) the median AUC of gadobutrol was 1.0 mmol·h/L, the median clearance was 0.1L/hr/kg, and the median elimination half life was 1.61h. In children aged 12-17 (n=46) the median AUC of gadobutrol was 1.2 mmol·h/L, the median clearance was 0.09 L/hr/kg, and the median elimination half life was 1.65h. Approximately 99% (median value) of the dose was recovered in the urine after 6 hours. A prolonged serum half life of gadobutrol is correlated with a reduction in creatinine clearance. In patients with mild-moderate renal impairment (80>CLCR>30 mL/min) the elimination half life was 5.8 ± 2.4 hours, the AUC was 4.0 ± 1.8 mmol·h/L, and complete recovery from the urine is seen within 72 hours. In patients with severe renal impairment (CLCR<30 mL/min) the elimination half life was 17.6 ± 6.2 hours, the AUC was 11.5 ± 4.3 mmol·h/L, and complete recovery from the urine is seen within 5 days. Physicians may consider the prompt initiation of hemodialysis following gadobutrol administration to aid elimination, in patients who are already receiving hemodialysis. After one dialysis session 68% of the initial dose is removed, after the second session 94%, and after the third session 98%.

来源:DrugBank

吸收、分配和排泄

静脉给药后，钆布醇迅速分布到细胞外空间。在给予0.1毫摩尔/千克体重的钆布醇剂量后，注射后2分钟在血浆中测得的平均浓度为0.59毫摩尔钆布醇/升，注射后60分钟为0.3毫摩尔钆布醇/升。钆布醇没有显示出任何特定的蛋白结合。在大鼠中，钆布醇不能透过完整的血脑屏障。

After intravenous administration, gadobutrol is rapidly distributed in the extracellular space. After a gadobutrol dose of 0.1 mmol/kg body weight, an average level of 0.59 mmol gadobutrol/L was measured in plasma 2 minutes after the injection and 0.3 mmol gadobutrol/L 60 minutes after the injection. Gadobutrol does not display any particular protein binding. In rats, gadobutrol does not penetrate the intact blood-brain barrier.

来源:Hazardous Substances Data Bank (HSDB)

制备方法与用途

钆布醇简介

钆布醇是一种含钆造影剂，主要用于核自旋层析成像（即MRI）。它于2000年在德国获得批准，作为Gadovist用于颅骨和脊柱磁共振成像(MRI)的造影增强。钆布醇由钆(Ⅲ)和10-(2,3-二羟基-1-(羟基甲基)丙基)-1,4,7,10-四氮杂环十二烷-1,4,7-三乙酸 (Butrol)构成的非离子络合物。它已成为临床上应用最广泛的MRI对比剂之一，并且是第六个获得美国食品药品监督管理局(FDA)批准用于中枢神经系统MRI的钆基对比剂。

用途

钆布醇是一种醇类有机化合物，适用于磁共振成像（MRI）检查作为显影剂使用。

制备 第一步

1. 取5.0g轮环滕宁(Ⅰ)和1.85g氯化锂于三口瓶中。
2. 加入30ml异丙醇，升温至80-85℃回流24小时。
3. 减压浓缩至干。在浓缩液中加入30ml无水THF搅拌溶清，再加入5.0g 4,4-二甲基-3,5,8-三氧杂二环[5.1.0]辛烷(Ⅱ)，升温回流5小时。
4. 减压浓缩至干，用甲基叔丁基醚回流析晶，过滤并以50℃真空干燥得中间体(Ⅳ)8.1g。

第二步

1. 8.0g中间体(Ⅳ)加入8ml纯化水搅拌溶清。
2. 另取7.37g氯乙酸溶于8ml纯化水中，于-5至-5℃加入3.27g一水合氢氧化锂，搅拌溶解。将氯乙酸锂溶液滴加到中间体(Ⅳ)溶液中，并升温至65℃。
3. 3小时内分批加入约2.8g一水合氢氧化锂，控制反应体系pH大于9，继续反应2小时。反应结束后，降温至室温，用盐酸调节pH为3.5，搅拌0.5h后加入160ml乙醇，升温回流，搅拌析晶5小时。
4. 降温至室温，过滤并真空干燥得中间体(Ⅳ)8.3g。

第三步

1. 8.2g中间体(Ⅳ)加入8ml纯化水搅拌溶解。调节pH为3.5，并加入3.02g氧化钆。
2. 升温至95℃，反应4小时后冷却至室温。
3. 用氢氧化锂调节至中性，滴加80ml乙醇，升温回流，搅拌析晶5小时。降温至室温，过滤并真空干燥得中间体(Ⅵ)即钆布醇粗品8.5g。

第四步

1. 取8.0g粗品加入8ml纯化水，升温70℃搅拌溶解。
2. 滴加80ml乙醇，1小时内加毕。滴加完毕后，升温至回流，搅拌析晶2小时，降温至室温，过滤并真空干燥得钆布醇7.1g。总收率为40.4%，HPLC纯度99.9%。

生物活性

Gadobutrol (Gadovist, Gadavist) 是一种非离子的大环的钆对比剂（GBCA），用于MRI中的组织造影增强。