Gadobenic acid   中文名称: 钆贝酸

Absorption, Distribution and Excretion
The distribution half-life of gadobutrate ions is short (expressed as mean ± standard deviation), ranging from 0.084 ± 0.012 to 0.605 ± 0.072 hours. The central compartment distribution volume ranges from 0.074 ± 0.017 to 0.158 ± 0.038 L/kg, while the area-estimated distribution volume ranges from 0.170 ± 0.016 to 0.282 ± 0.079 L/kg. The latter estimate is roughly equivalent to the average volume of human extracellular fluid. In vitro studies have shown that gadobutrate ions do not significantly bind to human serum proteins. /Gadobutrate Ion/ Pharmacokinetics were evaluated in rats, rabbits, dogs, and monkeys after intravenous injection of unlabeled gadobutrate diglucamine; biodistribution studies used (153)-Gd-labeled gadobutrate diglucamine. High-performance liquid chromatography (HPLC), X-ray fluorescence spectrometry (XRF), and gamma-ray spectroscopy (γ-ray diffraction) were used for analysis. The binding of gadobutrate ions to serum albumin in animals and humans was investigated using equilibrium dialysis. ... After intravenous injection, gadobutrate diglucamine is distributed in plasma, extracellular fluid, and the intercellular spaces of hepatocytes. Gadobutrate ions are primarily cleared from plasma via renal and bile excretion. Except for temporary accumulation in tissues relevant to its clearance, gadobutrate ions do not accumulate in specific tissues. Gadobutrate ions are not metabolized. Their binding affinity to plasma proteins is too weak to be detected by equilibrium dialysis. ...
Gadobutrate ions are primarily excreted by the kidneys, with 78% to 96% of the administered dose recovered in urine. The estimated total plasma and renal clearances of gadobutrate ions were similar, ranging from 0.093 ± 0.010 to 0.133 ± 0.270 L/hr/kg and 0.082 ± 0.007 to 0.104 ± 0.039 L/hr/kg, respectively. Its clearance was similar to that of substances filtered by the glomerulus. The mean elimination half-life was 1.17 ± 0.26 to 2.02 ± 0.60 hours. A small fraction of the administered dose (0.6% to 4%) was excreted via the bile route and in feces. The amount of gadobutrate meglumine secreted in human milk is currently unknown. Rat studies showed that less than 0.5% of the administered dose was passed from mother to newborn via breast milk. For more complete data on the absorption, distribution, and excretion of gadobutrate meglumine (7 types), please visit the HSDB records page.

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Metabolism/Metabolites
No biotransformation of gadobutrate ions was detected. In vivo studies showed that gadobutrate ions were dissociated to a very low degree, with less than 1% of the free chelate excreted solely in feces.

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Biological Half-Life
Gadobutrate ions are primarily excreted via the kidneys, with 78% to 96% of the administered dose excreted in the urine. …The mean elimination half-life ranges from 1.17 ± 0.26 to 2.02 ± 0.60 hours. …
…15 children scheduled for enhanced magnetic resonance imaging (MRI) due to suspected central nervous system disorders received a single intravenous injection of 0.1 mmol/kg gadobutrate dimethylglucamine. The terminal elimination half-life was 1.2 hours across all age groups. Eleven patients with end-stage renal disease (5 men and 6 women) who were on hemodialysis received a single intravenous injection of 0.2 mmol/kg of Multihance. The mean elimination half-life during dialysis was 1.21 ± 0.29 hours, compared to 42.4 ± 24.4 hours without dialysis. Twenty subjects with impaired renal function (6 men and 3 women, moderate renal impairment (urinary creatinine clearance > 30 to < 60 mL/min); 5 men and 6 women, severe renal impairment (urinary creatinine clearance > 10 to < 30 mL/min)) received a single intravenous injection of 0.2 mmol/kg of Multihance. The estimated mean elimination half-life for moderate and severe renal impairment groups was 6.1 ± 3.0 hours and 9.5 ± 3.1 hours, respectively, compared to 1.0 to 2.0 hours for healthy volunteers. The rapid distribution half-life of gadobutrate ions (expressed as mean ± standard deviation) ranged from 0.084 ± 0.012 to 0.605 ± 0.072 hours.

Toxicity Summary
Identification and Use: Gadobacterium dimeglumine (MultiHance) is a colorless to slightly yellow aqueous solution used for magnetic resonance imaging (MRI) examinations and is for intravenous injection only. Human Exposure and Toxicity: Gadobacterium-based contrast agents (GBCAs) increase the risk of developing renal systemic fibrosis (NSF) in patients with impaired drug clearance. GBCAs should be avoided in these patients unless diagnostic information is critical and cannot be obtained via non-contrast MRI or other examinations. NSF can lead to fatal or disabling systemic fibrosis affecting the skin, muscles, and internal organs. Patients with the following conditions are at highest risk of developing NSF: chronic severe kidney disease or acute kidney injury. Patients should be screened for acute kidney injury and other conditions that may impair kidney function. For patients at risk of chronic renal impairment (aged over 60 years, with hypertension, or diabetes), glomerular filtration rate (GFR) should be estimated by laboratory tests. For patients at high risk of renal systemic fibrosis (NSF), do not exceed the recommended MultiHance dose and allow sufficient time for drug clearance before re-administration. Allergic and anaphylactic reactions involving cardiovascular, respiratory, and/or skin manifestations have been reported. Some patients experienced circulatory failure and death. Cardiac arrhythmias were observed in patients treated with MultiHance in clinical trials. The mutagenicity of gadobemeglumine was investigated using a chromosomal aberration assay in cultured human lymphocytes. Regardless of metabolic activation, the drug did not induce an increase in the incidence of abnormal or polyploid cells under any treatment conditions. Therefore, it can be concluded that gadobemeglumine did not exhibit chromosome breakage-inducing or polyploid-inducing activity under these experimental conditions. Animal studies: A comprehensive series of toxicological safety studies were conducted to support the clinical application of injectable gadobemeglumine as a contrast agent for intravascular magnetic resonance imaging. Single-dose and multiple-dose toxicity, reproductive toxicity, and mutagenicity were assessed in rodents and non-rodents. Initial adverse clinical symptoms in monkeys were associated with a systemic exposure 34 times higher than that in humans (0.1 mmol/kg gadobemycin). Good systemic tolerability was observed in repeated-dose toxicity studies. In focal cerebral ischemia experiments with blood-brain barrier impairment, gadobemycin remained well-tolerated even at doses up to 10 times the maximum clinical dose for brain imaging (0.3 mmol/kg). Reproductive capacity in rats and the physiological and behavioral development of offspring were unaffected. However, intravenous administration of MultiHance at a dose of 2 mmol/kg/day (equivalent to 6 times the human dose based on body surface area) during organogenesis (days 6–18) has been shown to be teratogenic in rabbits, resulting in microphthalmia/microphthalmia and/or focal retinal folds in three fetuses from three different litters. Furthermore, intravenous administration of MultiHance at a dose of 3 mmol/kg/day (equivalent to 10 times the human dose based on body surface area) has been shown to increase intrauterine mortality in rabbits. Mutagenicity assays ruled out any genotoxicity of gadobutrazol. The following genotoxicity studies were all negative: 1) in vitro bacterial reverse mutation assay; 2) in vitro mammalian cell gene mutation assay; 3) in vitro chromosomal aberration assay; 4) in vitro unplanned DNA synthesis assay; and 5) rat micronucleus assay.

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Effects during pregnancy and lactation
◉ Overview of use during lactation
Gadobutrazol is safe for use in infants and therefore does not appear to pose a significant risk to breastfed infants. Guidelines developed by North American professional organizations state that breastfeeding mothers do not need to discontinue breastfeeding after receiving gadolinium-containing contrast agents.
◉ Effects on breastfed infants
No published information found as of the revision date.
◉ Effects on lactation and breast milk
No published information found as of the revision date.

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Interactions
MultiHance and other drugs may compete with tubule multispecific organic anion transporters (MOAT, also known as MRP2 or ABCC2). Therefore, MultiHance may prolong systemic exposure to drugs such as cisplatin, anthracyclines (e.g., doxorubicin, daunorubicin), vinca alkaloids (e.g., vincristine), methotrexate, etoposide, tamoxifen, and paclitaxel. The potential for long-term drug exposure in patients with reduced MOAT activity (e.g., Durbin-Johnson syndrome) should be considered.

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Non-human toxicity values
Mouse intravenous LD50: 5.7 mmol/kg (1 mL/min), 7.9 mmol/kg (0.2 mL/min)
Rat intravenous LD50: 6.6 mmol/kg (6 mL/min), 9.2 mmol/kg (1 mL/min)
Male rat intracisternal LD50: 0.42 mmol/kg
Female rat intracisternal LD50: 0.25 mmol/kg

[1]. Gadoxetic acid-enhanced MRI for the characterization of hepatocellular carcinoma: A systematic review and meta-analysis. J Magn Reson Imaging. 2017 Jan;45(1):281-290.

Gadobenate Dimeglumine is a gadolinium-based paramagnetic contrast agent. When placed in a magnetic field, gadoendazole generates a large magnetic moment, creating a strong local magnetic field that enhances the relaxation rate of nearby protons; therefore, the signal intensity of tissue images observed on magnetic resonance imaging (MRI) may be enhanced. Because this contrast agent is preferentially taken up by normal hepatocytes, MRI can enhance normal liver tissue while tumor tissue is not enhanced. Furthermore, since gadoendazole is excreted in bile, it can be used on MRI to visualize the biliary system.
See also: Gadobendic acid (preferred).

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Therapeutic Use
Contrast Agent
MultiHance is indicated for intravenous administration in adults and children aged 2 years and older for central nervous system (CNS) magnetic resonance imaging (MRI) to visualize lesions with abnormal blood-brain barrier or vascular abnormalities in the brain, spinal cord, and related tissues. /US Product Label Includes/
MultiHance is indicated for magnetic resonance angiography (MRA) to evaluate adult patients with known or suspected renal or aortoiliac-femoral occlusive vascular disease. /US Product Label Includes/
A study aimed to compare the efficacy of gadobenzamide (Multihance) with other commercially available MRI contrast agents in the detection of intracranial metastases…A retrospective evaluation was performed on MRI images from 22 patients enrolled in a previous phase II clinical trial of gadobenzamide. Each patient underwent two examinations: the first examination used one of three “control” contrast agents (gadopentate dimeglumine, gadodiamine, and gadoteric acid dimeglumine) at doses of 0.1 or 0.2 mmol/kg; the second examination used the same dose of gadobenzamide. All images were randomly assessed by two independent neuroradiologists, unaware of their group assignments, in both unmatched and matched formats, to determine the number and location of lesions. A third evaluator performed a quantitative evaluation on the complete set of available digitally recorded images (10 cases)…Results from the control contrast agents were pooled. Gadobacterium meglumine showed significantly higher sensitivity (93%-100%) for lesion detection than control contrast-enhanced imaging (65%-73%). Compared to non-enhanced contrast, gadobutramine consistently increased the lesion-brain tissue contrast of major lesions (+43% vs. +27%)… Gadobacterium meglumine has proven more effective than other control contrast agents in detecting intracranial metastatic lesions: both reviewers noted superior efficacy in terms of total lesion count, sensitivity, and positive predictive value. The higher relaxation rate of gadobutramine may explain its higher sensitivity in detecting central nervous system metastases using gadobutramine-enhanced MRI.
For more complete data on the therapeutic uses of gadobutramine (9 types), please visit the HSDB record page.

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Drug Warning
/Black Box Warning/ Warning: Renal-related systemic fibrosis. Gadolinium-based contrast agents (GBCAs) increase the risk of developing renal systemic fibrosis (NSF) in patients with impaired drug clearance. GBCAs should be avoided in these patients unless diagnostic information is critical and cannot be obtained via non-contrast MRI or other means. NSF can lead to fatal or disabling systemic fibrosis affecting the skin, muscles, and internal organs. Patients with chronic severe kidney disease (glomerular filtration rate <30 mL/min/1.73 m²) or acute kidney injury are at the highest risk of developing NSF. Patients should be screened for acute kidney injury and other conditions that may impair kidney function. For patients at risk of chronic renal impairment (e.g., age >60 years, hypertension, or diabetes), glomerular filtration rate (GFR) should be estimated by laboratory tests. For patients at high risk of NSF, do not exceed the recommended MultiHance dose and allow sufficient time for drug clearance before re-administering. Gadolinium-based contrast agents (GBCAs) increase the risk of developing renal systemic fibrosis (NSF) in patients with impaired drug clearance. GBCAs should be avoided in these patients unless diagnostic information is critical and cannot be obtained through non-contrast MRI or other examinations. The risk of gadolinium-based contrast agents (GBCAs) associated with renal systemic fibrosis (NSF) appears to be highest in patients with chronic severe kidney disease (glomerular filtration rate <30 mL/min/1.73 m²) and those with acute kidney injury. This risk appears to be lower in patients with chronic moderate kidney disease (glomerular filtration rate 30–59 mL/min/1.73 m²) and almost zero in patients with chronic mild kidney disease (glomerular filtration rate 60–89 mL/min/1.73 m²). NSF can lead to fatal or disabling fibrosis, affecting the skin, muscles, and internal organs. …Patients should be screened for acute kidney injury and other conditions that may impair kidney function. Acute kidney injury is characterized by a rapid (within hours to days) and usually reversible decline in kidney function, commonly occurring after surgery, severe infection, injury, or drug-induced nephrotoxicity. In cases of acute kidney injury, serum creatinine levels and estimated glomerular filtration rate (eGFR) may not reliably assess renal function. For patients at risk of chronic renal impairment (e.g., age > 60 years, diabetes, or chronic hypertension), glomerular filtration rate (GFR) should be estimated by laboratory testing. Factors that may increase the risk of renal systemic fibrosis (NSF) include repeated use or use of gadolinium-based contrast agents (GBCAs) at doses higher than recommended, and the degree of renal impairment at the time of exposure. The specific GBCA used and its dose should be documented. For patients at high risk of NSF, do not exceed the recommended MultiHance dose and allow sufficient time for drug clearance before re-administration. For patients undergoing hemodialysis, physicians may consider initiating hemodialysis immediately after GBCA administration to facilitate contrast agent clearance. The role of hemodialysis in preventing NSF is unclear. Allergic and anaphylactic reactions involving cardiovascular, respiratory, and/or skin manifestations have been reported. Some patients have experienced circulatory failure and death. In most cases, initial symptoms appear within minutes of MultiHance injection and subside with timely emergency treatment. Before administering MultiHance, ensure that trained personnel and medications are available to treat allergic reactions. If an allergic reaction occurs, discontinue MultiHance immediately and begin appropriate treatment. Furthermore, the risk of allergic reactions should be considered, especially in patients with a history of allergic reactions or asthma or other allergic conditions. Patients should be monitored for signs and symptoms of an allergic reaction during MultiHance injection and for 2 hours afterward.
FDA Pregnancy Risk Category: C / Risk cannot be ruled out. There are currently insufficient, well-controlled human studies, and animal studies have not shown any risk to the fetus or lack relevant data. Use of this drug during pregnancy may cause harm to the fetus; however, the potential benefits may outweigh the potential risks. /
For more complete data on drug warnings for gadobutrazol (15 total), please visit the HSDB Records page.

C22H28GDN3O11

667.7

668.096

113662-23-0

131700865

Hygroscopic powder

124 °C

1.21E-26mmHg at 25°C

213.94

2

14

17

37

726

0

[Gd+3].O(CC1C=CC=CC=1)CC(C(=O)[O-])N(CC(=O)[O-])CCN(CC(=O)[O-])CCN(CC(=O)[O-])CC(=O)[O-].[H+].[H+]

MXZROTBGJUUXID-UHFFFAOYSA-K

InChI=1S/C22H31N3O11.Gd/c26-18(27)10-23(6-7-24(11-19(28)29)12-20(30)31)8-9-25(13-21(32)33)17(22(34)35)15-36-14-16-4-2-1-3-5-16;/h1-5,17H,6-15H2,(H,26,27)(H,28,29)(H,30,31)(H,32,33)(H,34,35);/q;+3/p-3

2-[2-[carboxylatomethyl(carboxymethyl)amino]ethyl-[2-[carboxylatomethyl-(1-carboxy-2-phenylmethoxyethyl)amino]ethyl]amino]acetate;gadolinium(3+)

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。