Gadobutrol   中文名称: 钆布醇

Absorption, Distribution and Excretion
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. Following GBCA administration, gadolinium is present for months or years in the brain, bone, skin, and other organs. The mean AUC of gadobutrol in patients with normal renal function was 1.1 ± 0.1 mmol∙h/L, compared to 4.0 ± 1.8 mmol∙h/L in patients with mild to moderate renal impairment and 11.5 ± 4.3 mmol∙h/L in patients with severe renal impairment.
Gadobutrol is excreted in an unchanged form via the kidneys. Within two hours after intravenous administration more than 50% and within 12 hours more than 90% of the given dose is eliminated via the urine. Extra-renal elimination is negligible.
In children aged 2 to 17, the body weight-normalized median total volumes of distribution (L/kg) were estimated to be 0.20 (0.12, 0.28) for all ages, 0.24 (0.20, 0.28) in the 2 to 6-year age group, 0.19 (0.14, 0.23) in the 7 to 11 year age group and 0.18 (0.092, 0.23) in the 12 to 17 year age group.
In healthy subjects, renal clearance is 1.1 - 1.7mL/(min·kg). Clearance was observed to be slightly lower in elderly subjects, when using a 0.1 mmol/kg dose.
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.
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.

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Metabolism / Metabolites
Gadobutrol is not metabolized.

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Biological Half-Life
For adult patients, the half-life was estimated to be 1.80 (1.20, 6.55) hours. For pediatric aged 0 to <2 years, 2 to 6 years, 7 to 11 years, and 12 to < 18 years, the half-life was calculated to be 2.91 (1.60, 12.4), 1.91 (1.04, 2.70), 1.66 (0.91, 2.71), and 1.68 (1.31, 2.48) hours respectively.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Gadobutrol is one of the most stable gadolinium agents, theoretically making it one of the safer drugs to use during breastfeeding. Guidelines developed by several professional organizations state that breastfeeding need not be disrupted after a nursing mother receives a gadolinium-containing contrast medium. However, because there is no published experience with gadobutrol during breastfeeding, other agents may be preferred, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
No information is available on the protein binding of gadobutrol.

Gadobutrol is a second-generation extracellular non-ionic macrocyclic GBCA (gadolinium-based contrast agent) used in magnetic resonance imaging (MRI) in adults and children older than 2 years of age. Due to its physicochemical properties, gadobutrol is formulated at twice the gadolinium ion concentration compared to other GBCA and thus requires a lesser injection volume. Like other GBCA, gadobutrol usage carries the risk of nephrogenic systemic fibrosis (NSF) due to the dissociation of gadolinium from the chelates, although gadobutrol tends to have a lower risk of NSF thanks to the macrocyclic structures that limit dechelation of gadolinium.
Gadobutrol is a Gadolinium-based Contrast Agent. The mechanism of action of gadobutrol is as a Magnetic Resonance Contrast Activity.
Gadobutrol is a gadolinium-based, hydrophilic, macrocyclic, electrically neutral contrast agent used in contrast-enhanced MRI (CE-MRI). Gadobutrol is a non-ionic, paramagnetic complex consisting of gadolinium (Gd3+) chelated with the macrocyclic compound dihydroxy-hydroxymethylpropyl-tetraazacyclododecane-triacetic acid (butrol). Following intravenous administration, gadobutrol may increase MRI sensitivity for the detection of tumors and inflammatory and demyelinating diseases of the central nervous system (CNS) that are associated with areas with blood-brain barrier defects due to altered perfusion or an enlarged extracellular space. This agent is eliminated in an unchanged form via the kidneys; extra-renal elimination is negligible.
See also: Gadolinium Cation (3+) (has active moiety).

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Drug Indication
Gadobutrol is indicated for use with magnetic resonance imaging for the following diagnostic processes: - To detect and visualize areas with disrupted blood-brain barrier and/or abnormal vascularity of the central nervous system in adult and pediatric patients, including term neonates. - To assess the presence and extent of malignant breast disease in adult patients - To evaluate known or suspected supra-aortic or renal artery disease in adult and pediatric patients, including term neonates - To assess myocardial perfusion (under stress and at rest) and late gadolinium enhancement in adult patients with known or suspected coronary artery disease
FDA Label
Diagnostic evaluation of tissue pathologies with contrast-enhanced magnetic resonance imaging (MRI)

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Mechanism of Action
In MRI, visualization of normal and pathological tissue depends in part on variations in the radiofrequency signal intensity that occur with differences in proton density, the spin-lattice or longitudinal relaxation times (T1), and the spin-spin or transverse relaxation time (T2). When placed in a magnetic field, gadobutrol shortens the T1 and T2 relaxation times. The extent of decrease of T1 and T2 relaxation times, and therefore the amount of signal enhancement obtained from gadobutrol, is based upon several factors including the concentration of gadobutrol in the tissue, the field strength of the MRI system, and the relative ratio of the longitudinal and transverse relaxation times. At the recommended dose, the T1 shortening effect is observed with the greatest sensitivity in T1-weighted magnetic resonance sequences. In T2*-weighted sequences, the induction of local magnetic field inhomogeneities by the large magnetic moment of gadolinium and at high concentrations (during bolus injection) leads to a signal decrease.

C18H31GDN4O9

604.71

605.133

138071-82-6

6102852

White to off-white solid powder

194

3

13

7

32

532

2

C1CN(CCN(CCN(CCN1C(CO)C(CO)O)C(=O)[O-])C(=O)[O-])C(=O)[O-].[Ga+3]

ZPDFIIGFYAHNSK-CTHHTMFSSA-K

InChI=1S/C18H34N4O9.Gd/c23-12-14(15(25)13-24)22-7-5-20(10-17(28)29)3-1-19(9-16(26)27)2-4-21(6-8-22)11-18(30)31;/h14-15,23-25H,1-13H2,(H,26,27)(H,28,29)(H,30,31);/q;+3/p-3/t14-,15-;/m1./s1

2-[4,10-bis(carboxylatomethyl)-7-[(2R,3S)-1,3,4-trihydroxybutan-2-yl]-1,4,7,10-tetrazacyclododec-1-yl]acetate;gadolinium(3+)

Gadobutrol, Gadograf ZK 135079 Gd-DO3A-butrol

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。