Gadoxetate Disodium   中文名称: 钆塞酸二钠

Absorption, Distribution and Excretion
Gadoxetate disodium is equally eliminated via the renal and hepatobiliary routes. The mean terminal elimination half-life of gadoxetate disodium (0.01 to 0.1 mmol/kg) has been observed in healthy volunteers of 22-39 years of age to be 0.91 to 0.95 hour. Clearance appeared to decrease slightly with increasing age. The pharmacokinetics are dose-linear up to a dose of 0.4 mL/kg (0.1 mmol/kg), which is 4 times the recommended dose.
After intravenous administration, the plasma concentration time profile of gadoxetate disodium is characterized by a bi-exponential decline. The total distribution volume of gadoxetate disodium at steady state is about 0.21 L/kg (extracellular space); plasma protein binding is less than 10%. Gadoxetate disodium does not pass the intact blood-brain barrier and diffuses through the placental barrier.
In lactating rats given 0.1 mmol/kg [153Gd] gadoxetate disodium, less than 0.5% of the total administered radioactivity was transferred to the neonates via maternal milk, mostly within 2 hours.

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Metabolism / Metabolites
Gadoxetate disodium is not metabolized.

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Biological Half-Life
The mean terminal elimination half-life of gadoxetate disodium (0.01 to 0.1 mmol/kg) has been observed in healthy volunteers of 22-39 years of age to be 0.91 to 0.95 hour.

Toxicity Summary
IDENTIFICATION: Gadoxetate disodiumis a gadolinium-based contrast agent indicated for intravenous use in T1-weighted magnetic resonance imaging (MRI) of the liver to detect and characterize lesions in adults with known or suspected focal liver disease. HUMAN EXPOSURE AND TOXICITY: The most frequent (>/=0.5%) adverse reactions associated with the use of EOVIST are nausea, headache, feeling hot, dizziness, and back pain. Patients with liver lesions received gadoxetate disodium-enhanced liver magnetic resonance imaging (MRI). Adverse events (AEs) were recorded and evaluated with regard to a potential drug relationship. Subgroup analyses were run on patients with special medical history. Worldwide spontaneous AEs and adverse drug reactions (ADRs) from postmarketing safety surveillance were analyzed. A total of 1989 patients were included in the clinical development program. A total of 1581/1989 (79.5%) patients received the finally approved dose of 0.025 mmol/kg body weight. 10.1% of patients reported AEs, 4.1% were classified as related AEs. Nausea and headache were the most frequently reported related AEs, with 1.1% each. Age, history of contrast media allergy, liver cirrhosis, or impaired liver or renal function did not significantly impact the frequency and type of AEs. The postmarketing safety surveillance database encompassed more than 2.2 million patients. Nausea was the most frequent ADR, with a reporting rate of 0.00652%; all other symptoms were below 0.004%. Gadoxetate disodium for liver MRI has an excellent safety profile Gadoxetate disodium-associated transient severe respiratory motion artifact is significantly more common after 20-mL administration (2 mL/s) and occurs significantly more often in patients with chronic obstructive pulmonary disease. The volume-related effect suggests a nonallergiclike mechanism. ANIMAL STUDIES: A dose-related increase in QTc which was resolved by 30 minutes post dosing was observed in dogs when given a single dose of EOVIST. The increase was noted when given in doses equal to or greater than 0.1 mmol/kg (2.2 times the human dose). Maximum increase in QTcF was equal to or less than 20 ms at doses up to 0.5 mmol/kg (11 times the human dose). Animal reproductive and developmental toxicity studies were done in rats and rabbits. Gadoxetate disodium was not teratogenic when given intravenously during organogenesis to pregnant rats at doses up to 32 times the recommended single human dose (mmol/m2 basis). However, an increase in preimplantation loss was noted at 3.2 times the human dose (mmol/m2 basis). Compared to untreated controls, rates of postimplantation loss and absorption increased and litter size decreased when pregnant rabbits received gadoxetate disodium at doses 26 times the recommended human single dose (mmol/m2 basis). This occurred without evidence of maternal toxicity. Because pregnant animals received repeated daily doses of EOVIST, their overall exposure was significantly higher than that achieved with the standard single dose administered to humans.

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Interactions
An interaction study in healthy subjects demonstrated that the co-administration of the OATP inhibitor erythromycin did not influence efficacy and pharmacokinetics of EOVIST. No further clinical interaction studies with other medicinal products have been performed.
Patients with liver lesions received gadoxetate disodium-enhanced liver magnetic resonance imaging (MRI). Adverse events (AEs) were recorded and evaluated with regard to a potential drug relationship. Subgroup analyses were run on patients with special medical history. Worldwide spontaneous AEs and adverse drug reactions (ADRs) from postmarketing safety surveillance were analyzed. A total of 1989 patients were included in the clinical development program. A total of 1581/1989 (79.5%) patients received the finally approved dose of 0.025 mmol/kg body weight. 10.1% of patients reported AEs, 4.1% were classified as related AEs. Nausea and headache were the most frequently reported related AEs, with 1.1% each. Age, history of contrast media allergy, liver cirrhosis, or impaired liver or renal function did not significantly impact the frequency and type of AEs. The postmarketing safety surveillance database encompassed more than 2.2 million patients. Nausea was the most frequent ADR, with a reporting rate of 0.00652%; all other symptoms were below 0.004%. Gadoxetate disodium for liver MRI has an excellent safety profile.

[1]. Preclinical evaluation of Gd-EOB-DTPA as a contrast agent in MR imaging of the hepatobiliary system. Radiology. 1992 Apr;183(1):59-64.

[2]. Estimation of liver function using T1 mapping on Gd-EOB-DTPA-enhanced magnetic resonance imaging. Invest Radiol. 2011 Apr;46(4):277-83.

[3]. Gd-EOB-DTPA enhanced MRI for hepatocellular carcinoma: quantitative evaluation of tumor enhancement in hepatobiliary phase. Magn Reson Med Sci. 2005;4(1):1-9.

[4]. Use of gadoxetate disodium in patients with chronic liver disease and its implications for liver imaging reporting and data system (LI-RADS). J Magn Reson Imaging. 2019 May;49(5):1236-1252.

[5]. Troubleshooting Arterial-Phase MR Images of Gadoxetate Disodium-Enhanced Liver. Korean J Radiol. 2015 Nov-Dec;16(6):1207-15.

[6]. Gadolinium deposition in the liver and brain in a rat model with liver fibrosis after intravenous administration of gadoxetate disodium. Heliyon. 2024 Mar 8;10(6):e27419.

Gadoxetate Disodium is a paramagnetic contrast agent consisting of the disodium salt of the gadolinium ion chelated with the lipophilic moiety ethoxybenzyl (EOB) bound to diethylenetriamine pentaacetic acid (DTPA). When placed in a magnetic field, gadolinium produces a large magnetic moment and so a large local magnetic field, which can enhance the relaxation rate of nearby protons; as a result, the signal intensity of tissue images observed with magnetic resonance imaging (MRI) may be enhanced. Because this agent is preferentially taken up by normal functioning hepatocytes, normal hepatic tissue is enhanced with MRI while tumor tissue is unenhanced. In addition, because this agent is excreted in the bile, it may be used to visualize the biliary system using MRI.
See also: Gadoxetate Disodium (annotation moved to).

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Therapeutic Uses
EOVIST Injection is a gadolinium-based contrast agent indicated for intravenous use in T1-weighted magnetic resonance imaging (MRI) of the liver to detect and characterize lesions in adults with known or suspected focal liver disease.

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Drug Warnings
/BOXED WARNING/ WARNING: NEPHROGENIC SYSTEMIC FIBROSIS (NSF) Gadolinium-based contrast agents (GBCAs) increase the risk for 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. The risk for NSF appears highest among patients with: Chronic, severe kidney disease (GFR < 30 mL/min/1.73m2), 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 (for example, age >60 years, hypertension or diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing.
Anaphylactoid and anaphylactic reactions with cardiovascular, respiratory and cutaneous manifestations, ranging from mild to severe reactions, including shock have uncommonly occurred following EOVIST administration. Before EOVIST administration, assess all patients for any history of a reaction to contrast media, a history of bronchial asthma and/or a history of allergic disorders. These patients may have an increased risk for a hypersensitivity reaction to EOVIST; weigh the benefits of EOVIST MRI carefully against the risks in these clinical settings. Administer EOVIST 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 EOVIST have occurred within half an hour after administration. Delayed reactions (hours up to several days) may occur. Observe patients for signs and symptoms of hypersensitivity reactions during and following EOVIST administration. Treat these reactions with standard medications for hypersensitivity reactions.
Serum iron determination using complexometric methods (for example, Ferrocine complexation method) may result in falsely high or low values for up to 24 hours after EOVIST administration.
Severe renal or hepatic failure may impair EOVIST imaging performance. In patients with end-stage renal failure, hepatic contrast was markedly reduced and was attributed to elevated serum ferritin levels. In patients with abnormally high (>3 mg/dL) serum bilirubin, reduced hepatic contrast was observed. If EOVIST is used in these patients, complete MR imaging no later than 60 minutes after EOVIST administration and use a paired non-contrast and contrast MRI image set for diagnosis.
For more Drug Warnings (Complete) data for Gadoxetate disodium (6 total), please visit the HSDB record page.

C23H33N3O11.GD.2[NA+]

730.751220000001

726.076

135326-22-6

770677-60-6;135326-22-6 (sodium);

91754427

White to off-white solid powder

220

0

14

4

40

746

0

CCOC1=CC=C(C=C1)CC(CN(CCN(CC(=O)[O-])CC(=O)[O-])CC(=O)[O-])N(CC(=O)[O-])CC(=O)[O-].[Gd+3].[Na+].[Na+]

SLYTULCOCGSBBJ-UHFFFAOYSA-I

InChI=1S/C23H33N3O11.Gd.2Na/c1-2-37-18-5-3-16(4-6-18)9-17(26(14-22(33)34)15-23(35)36)10-24(11-19(27)28)7-8-25(12-20(29)30)13-21(31)32;;;/h3-6,17H,2,7-15H2,1H3,(H,27,28)(H,29,30)(H,31,32)(H,33,34)(H,35,36);;;/q;+3;2*+1/p-5

disodium;2-[[2-[bis(carboxylatomethyl)amino]-3-(4-ethoxyphenyl)propyl]-[2-[bis(carboxylatomethyl)amino]ethyl]amino]acetate;gadolinium(3+)

Gd EOB DTPA ZK 139834 ZK139834 GdEOBDTPA ZK-139834Gd-EOB-DTPA

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中，避免吸湿/受潮。

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

H2O : ≥ 100 mg/mL (~137.80 mM)
DMSO : ~24 mg/mL (~33.07 mM)

配方 1 中的溶解度: ≥ 2.4 mg/mL (3.31 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 24.0 mg/mL澄清的DMSO储备液加入到400 μL PEG300中，混匀；再向上述溶液中加入50 μL Tween-80，混匀；然后加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.4 mg/mL (3.31 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 24.0mg/mL澄清的DMSO储备液加入到900μL 20％SBE-β-CD生理盐水中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.4 mg/mL (3.31 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 24.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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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。