Gadobutrol gradually reduces cell density under neutron irradiation as concentration increases [1].

In female C57BL/6 N mice, intrathecal injection of 200 mM dobutril administered once a week can markedly improve intracerebroventricular cell signaling [2].

Cell viability assay [1]
Cell Types: Human melanoma cell line Sk-Mel-28
Tested Concentrations: 0-30 mM
Incubation Duration: 1 hour
Experimental Results: Cell density diminished to 26% at 30 mM, compared with cells without gadobutrol Density drops to 80% under neutron irradiation.

Animal/Disease Models: Female C57BL/6 N mice, 11-13 weeks, 21-23 g)[2]
Doses: 200 mM
Route of Administration: intravenous (iv) (iv)injection; once; one week
Experimental Results: cells in habenula, hippocampal formation and locus coeruleus Signal boost.

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.

[1]. Gadolinium neutron capture therapy (GdNCT) of melanoma cells and solid tumors with the magnetic resonance imaging contrast agent Gadobutrol. Invest Radiol. 1999 Feb;34(2):126-33.

[2]. Gadobutrol enhances T1-weighted MRI of nerve cells. Toxicol Lett. 2019 Jun 15;308:17-23.

[3]. Cheng KT. Gadobutrol. Molecular Imaging and Contrast Agent Database (MICAD).

Gadolinol 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, gadolinol has twice the gadolinium ion concentration of other GBCAs, thus requiring a smaller injection volume. Like other GBCAs, gadolinol 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 gadolinol. Gadolinol is a gadolinium-based contrast agent. Its mechanism of action is as a magnetic resonance contrast agent. Gadolinol 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).

C18H31N4O9GD

604.71

605.133

770691-21-9

Gadobutrol hydrate;198637-52-4

6102852

White to off-white solid powder

3

13

7

32

532

2

C1CN(CCN(CCN(CCN1CC(=O)[O-])CC(=O)[O-])[C@H](CO)[C@@H](CO)O)CC(=O)[O-].[Gd+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+)

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)

H2O : ~20 mg/mL (~33.07 mM)

Solubility in Formulation 1: 50 mg/mL (82.68 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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