Absorption, Distribution and Excretion
Following intravenous injection, gadobutrol rapidly distributes into the extracellular space. After injection of 0.1 mmol/kg body weight of gadobutrol, the mean plasma concentration was 0.59 mmol/L at 2 minutes and 0.3 mmol/L at 60 minutes. Gadobacterium does not bind to any protein. Following injection of gadolinium contrast agents, gadolinium can persist in the brain, bone, skin, and other organs for months or years. The mean AUC of gadobutrol in patients with normal renal function was 1.1 ± 0.1 mmol∙h/L, in patients with mild to moderate renal impairment it was 4.0 ± 1.8 mmol∙h/L, and in patients with severe renal impairment it was 11.5 ± 4.3 mmol∙h/L. Gadobacterium is excreted unchanged via the kidneys. Within 2 hours after intravenous administration, more than 50% of the administered dose is excreted in the urine; within 12 hours, more than 90% of the administered dose is excreted in the urine. Extrarenal clearance is negligible. In children aged 2 to 17 years, the estimated median volume of distribution (L/kg) normalized to body weight was: 0.20 (0.12, 0.28) for all age groups, 0.24 (0.20, 0.28) for 2 to 6 years, 0.19 (0.14, 0.23) for 7 to 11 years, and 0.18 (0.092, 0.23) for 12 to 17 years. In healthy subjects, renal clearance was 1.1–1.7 mL/(min·kg). Clearance was slightly lower in older subjects at a dose of 0.1 mmol/kg. Following intravenous administration, gadobutrol rapidly distributes into the extracellular space. Following injection of 0.1 mmol/kg body weight gadobutrol, the mean plasma concentration of gadobutrol was 0.59 mmol/L 2 minutes post-injection and 0.3 mmol/L 60 minutes post-injection. Gadobacterium does not possess any specific protein-binding capacity. In rats, gadobutrol cannot cross the intact blood-brain barrier. In lactating rat studies, the gadobutrol content in breast milk was less than 0.1% of the intravenously administered dose, and gastrointestinal absorption was poor (approximately 5% of the oral dose was excreted in the urine). In lactating rats receiving 0.5 mmol/kg intravenous [153Gd]-gadobacterium, 0.01% of the total administered radioactivity was transferred to pups via breast milk within 3 hours post-administration. Gadobutrol is not metabolized.

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Biological Half-Life
For adult patients, the estimated half-life is 1.80 (1.20, 6.55) hours. For children aged 0 to <2 years, 2 to 6 years, 7 to 11 years, and 12 to <18 years, the calculated half-lives are 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
◉ Overview of Use During Lactation
Gadobutrol is one of the most stable gadolinium contrast agents and is theoretically one of the safest drugs for use during lactation. Guidelines from multiple professional organizations indicate that breastfeeding mothers do not need to interrupt breastfeeding after receiving gadolinium-containing contrast agents. However, since there is currently no published experience regarding the use of gadobutrol during lactation, other contrast agents may be preferred, especially when breastfeeding newborns or premature infants. ◉ 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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Protein Binding
There is currently no information regarding the protein binding of gadobutrol.

Gadobutrol is a second-generation extracellular nonionic macrocyclic gadolinium-based contrast agent (GBCA) used for magnetic resonance imaging (MRI) in adults and children aged 2 years and older. Due to its physicochemical properties, Gadobutrol has twice the gadolinium ion concentration of other GBCAs, thus requiring a smaller injection volume. Like other GBCAs, Gadobutrol carries a risk of renal systemic fibrosis (NSF) due to gadolinium dissociation from its chelates; however, its macrocyclic structure restricts gadolinium dissociation, resulting in a generally lower risk of NSF with Gadobutrol. Gadobutrol is a gadolinium-based contrast agent. Its mechanism of action is as a magnetic resonance contrast agent. Gadobutrol is a gadolinium-based hydrophilic macrocyclic compound, electrically neutral, used for contrast-enhanced magnetic resonance imaging (CE-MRI). Gadobacterol is a nonionic paramagnetic complex composed of gadolinium (Gd3+) chelated with the macrocyclic compound dimethylolpropyltetraazacyclododecanetriacetic acid (gadobacterol). Following intravenous injection, gadobuterol enhances the detection rate of central nervous system (CNS) tumors, as well as inflammatory and demyelinating diseases associated with areas of blood-brain barrier defect (due to perfusion alterations or extracellular space widening) on magnetic resonance imaging. The drug is excreted unchanged via the kidneys. Extrarenal excretion is negligible.
See also: Gadolinium cation (3+) (with active moiety).
Indications
Gadobacterol is indicated for use on magnetic resonance imaging in the following diagnostic procedures: - Detection and visualization of areas of blood-brain barrier disruption and/or central nervous system vascular abnormalities in adult and pediatric patients, including full-term newborns. - Assess the presence and extent of breast malignancy in adult patients. - Assess known or suspected supra-aortic arch or renal artery disease in adult and pediatric patients (including full-term newborns). - Assess myocardial perfusion (both under load and at rest) and delayed gadolinium enhancement in adult patients with known or suspected coronary artery disease. FDA Label. Contrast-Enhanced Magnetic Resonance Imaging (MRI) for Diagnostic Assessment of Tissue Lesions. Mechanism of Action: In MRI, the imaging of normal and diseased tissues depends on variations in radiofrequency signal intensity, which are caused by differences in proton density, spin-lattice or longitudinal relaxation time (T1), and spin-spin or transverse relaxation time (T2). When placed in a magnetic field, gadobutrol shortens both T1 and T2 relaxation times. The degree of shortening of T1 and T2 relaxation times, and the resulting increase in gadobutrol signal, depends on a variety of factors, including the concentration of gadobutrol in the tissue, the magnetic field strength of the MRI system, and the relative ratio of longitudinal and transverse relaxation times. At the recommended dose, the T1 shortening effect is most significant in T1-weighted magnetic resonance sequences. In T2-weighted sequences, signal attenuation occurs due to the large magnetic moment of gadolinium and the local magnetic field inhomogeneity caused by high concentration (during bolus injection).

C18H31GDN4O9

604.71

605.133

138071-82-6

6102852

White to off-white solid powder

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

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)