- Accession Number
- Small Molecule
Intravenous 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. It may help visualize and detect vascular abnormalities in the blood brain barrier (BBB) and central nervous system (CNS).
In patients with impaired renal function, gadolinium based contrast agents increase the risk of nephrogenic systemic fibrosis (NSF). A physician should be contacted if symptoms of NSF are encountered, such as dark or red patches on the skin; stiffness in joints; trouble moving, bending or straightening arms, hands, legs or feet; burning, itching, swelling, scaling, hardening and tightening of skin; pain in hip bones or ribs; or muscle weakness.
Common adverse reactions that may be experienced include headache, nausea, feeling hot, abnormal taste, and warmth, burning or pain local to the injection site.
General precautions should be taken in patients who are pregnant or breastfeeding, or who have a history of allergic reaction to contrast media, bronchial asthma or an allergic respiratory disorder.
- gadolinium(III) 2,2',2''-(10-((2R,3S )-1,3,4-trihydroxybutan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate
- External IDs
- BAY86-4875 / ZK-135079
- Active Moieties
Name Kind UNII CAS InChI Key Gadolinium cation (3+) ionic AZV954TZ9N 22541-19-1 RJOJUSXNYCILHH-UHFFFAOYSA-N
- Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Gadavist Injection 604.72 mg/1mL Intravenous Bayer HealthCare Pharmaceuticals Inc. 2011-03-14 Not applicable Gadovist 1.0 Solution 604.72 mg Intravenous Bayer 2004-01-30 Not applicable
- International/Other Brands
- Gadovist (Bayer Schering Pharma)
- CAS number
- Average: 604.72
- Chemical Formula
- InChI Key
- IUPAC Name
For diagnostic use only. Indicated for adults and children age 2 and over for contrast enhancement during cranial and spinal MRI, and for contrast-enhanced magnetic resonance angiography (CE-MRA). Gadobutrol is particularly suited for the detection of very small lesions and for the visualization of tumors that do not readily take up contrast media. It may be a desired agent when the exclusion or demonstration of an additional pathology may influence the choice of therapy or patient management. It may also be suitable for perfusion studies in the diagnosis of stroke, detection of focal cerebral ischemia, and in studies of tumor perfusion.
- Associated Conditions
Even at low concentrations Gadobutrol can lead to distinct shortening of relaxation times of protons in plasma. At physiological conditions (pH=7, temperature=37°C), and 1.5T, the relaxivity (r1) is 5.2L/(mmol·sec) based on the relaxation times (T1), while the relativity (r2) is 6.1L/(mmol·sec) based on relaxation times (T2).
Magnetic field strength has only slight influence on relaxivities.
Drug concentration and r1 relaxivity may contribute to a T1 shortening effect, which may improve tissue visualization.
- Mechanism of action
MRI tissue visualization is dependent, in part, on variations in intensity of radiofrequency signals which occur due to differences in proton density, differences of the spin-lattice or longitudinal relaxation times (T1), and differences in the spin-spin or transverse relaxation times (T2).
Gadolinium shortens T1 and T2 relaxation times. Greater signal enhancement is achieved with increased shortening of T1 and T2. The extent to which Gadolinium can shorten T1 and T2 is influenced by concentration in tissue, MRI field strength, and the relative ratio of transverse and longitudinal relaxation times.
The recommended dose produced the greatest sensitivity of T1 shortening effect in T1-weighted magnetic resonance sequences. In T2-weighted sequences, the large magnetic moment of gadolinium induced local magnetic field inhomogenenities.
At high concentrations used during bolus injections, T2-weighted sequences show a signal decrease.
With normal renal function, the AUC is 1.1 ± 0.1 mmol·h/L.
- Volume of distribution
Rapid distribution to extracellular space occurs after intravenous administration.
After a dose of 0.1mmol/kg body weight, an average plasma level of 0.59 mmol/L was measured 2 minutes post injection, and 0.3mmol/L 60 minutes post injection.
- Protein binding
No particular protein binding is displayed.
Gadobutrol is not metabolized.
- Route of elimination
Excreted unchanged via glomerular filtration by the kidneys. Extrarenal elimination is negligible.
- Half life
1.81 hours (1.33-2.13 hours).
In healthy subjects, renal clearance is 1.1 - 1.7mL/(min·kg). Within 2 hours of intravenous injection more than 50% is eliminated via the urine. Within 12 hours more than 90% of the given dose is eliminated.
Clearance was observed to be slightly lower in elderly subjects, when using a 0.1mmol/kg dose.
In the pediatric population, the median AUC, clearance and elimination half life was observed to be similar across the age range of 2-17, based on a population pharmacokinetic analysis of 130 pediatric subjects aged 2-17. In children aged 2-6 (n=45) the median AUC of gadobutrol was 0.8 mmol·h/L, the median clearance was 0.13L/hr/kg, and the median elimination half life was 1.75h. In children aged 7-11 (n=39) the median AUC of gadobutrol was 1.0 mmol·h/L, the median clearance was 0.1L/hr/kg, and the median elimination half life was 1.61h. In children aged 12-17 (n=46) the median AUC of gadobutrol was 1.2 mmol·h/L, the median clearance was 0.09 L/hr/kg, and the median elimination half life was 1.65h. Approximately 99% (median value) of the dose was recovered in the urine after 6 hours.
A prolonged serum half life of gadobutrol is correlated with a reduction in creatinine clearance. In patients with mild-moderate renal impairment (80>CLCR>30 mL/min) the elimination half life was 5.8 ± 2.4 hours, the AUC was 4.0 ± 1.8 mmol·h/L, and complete recovery from the urine is seen within 72 hours. In patients with severe renal impairment (CLCR<30 mL/min) the elimination half life was 17.6 ± 6.2 hours, the AUC was 11.5 ± 4.3 mmol·h/L, and complete recovery from the urine is seen within 5 days.
Physicians may consider the prompt initiation of hemodialysis following gadobutrol administration to aid elimination, in patients who are already receiving hemodialysis. After one dialysis session 68% of the initial dose is removed, after the second session 94%, and after the third session 98%.
Lethality was observed in rodents after a single intravenous administration of 20 mmol/kg. This represents a dose of at least 2 orders of magnitude higher than the standard single diagnostic dose in humans (0.1 mmol/kg).
No carcinogenicity studies have been conducted.
No mutagenesis was observed in vitro in reverse mutation tests in bacteria, or in the HGPRT (hypoxanthine-guanine phosphoribosyl transferase) test using Chinese hamster V79 cells. Similarly, no mutagenesis was seen in chromosome abberation tests of human peripheral blood lymphocytes. It was also negative in in-vivo micronucleus tests in mice following a 0.5mmol/kg intravenous injection.
No fertility or reproductive impairment was observed in male and female rates given doses 12.2 times human equivalent doses, based on body surface area.
Intolerance reactions local to the injection site have been observed in rabbits after paravenous administration, and are associated with the infiltration of inflammatory cells, suggesting the possibility of local irritation if the contrast medium leaks around veins in a clinical setting.
- Affected organisms
- Humans and other mammals
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
- Synthesis Reference
Orlin Petrov, Peter Blaszkiewicz, "Process for mono- and 1,7-bis-N-.beta.-hydroxyalkylation of cyclene; N-.beta.-hydroxyalkyl-1,4,7,10-tetraazacyclododecane-lithium-salt complexes and the use of the complexes for the production of gadobutrol and analogs." U.S. Patent US5994536, issued May, 1998.US5994536
- General References
- Scott LJ: Gadobutrol: a review of its use for contrast-enhanced magnetic resonance imaging in adults and children. Clin Drug Investig. 2013 Apr;33(4):303-14. doi: 10.1007/s40261-013-0066-0. [PubMed:23435930]
- Wack C, Steger-Hartmann T, Mylecraine L, Hofmeister R: Toxicological safety evaluation of gadobutrol. Invest Radiol. 2012 Nov;47(11):611-23. doi: 10.1097/RLI.0b013e318263f128. [PubMed:23011188]
- Kunnemeyer J, Terborg L, Nowak S, Scheffer A, Telgmann L, Tokmak F, Gunsel A, Wiesmuller G, Reichelt S, Karst U: Speciation analysis of gadolinium-based MRI contrast agents in blood plasma by hydrophilic interaction chromatography/electrospray mass spectrometry. Anal Chem. 2008 Nov 1;80(21):8163-70. doi: 10.1021/ac801264j. Epub 2008 Sep 27. [PubMed:18821778]
- External Links
- ATC Codes
- V08CA09 — Gadobutrol
- AHFS Codes
- 36:89.00* — Other Diagnostics
- FDA label
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- Clinical Trials
- Not Available
- Not Available
- Dosage forms
Form Route Strength Injection Intravenous 604.72 mg/1mL Solution Intravenous 604.72 mg
- Not Available
Patent Number Pediatric Extension Approved Expires (estimated) US5980864 No 1996-11-09 2016-11-09
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.0496 mg/mL ALOGPS logP 0.35 ALOGPS logP -4.6 ChemAxon logS -4.2 ALOGPS pKa (Strongest Acidic) 0.99 ChemAxon pKa (Strongest Basic) -3 ChemAxon Physiological Charge 0 ChemAxon Hydrogen Acceptor Count 9 ChemAxon Hydrogen Donor Count 3 ChemAxon Polar Surface Area 181.08 Å2 ChemAxon Rotatable Bond Count 10 ChemAxon Refractivity 143.47 m3·mol-1 ChemAxon Polarizability 45.39 Å3 ChemAxon Number of Rings 4 ChemAxon Bioavailability 1 ChemAxon Rule of Five No ChemAxon Ghose Filter No ChemAxon Veber's Rule No ChemAxon MDDR-like Rule Yes ChemAxon
- Predicted ADMET features
Property Value Probability Human Intestinal Absorption - 0.9703 Blood Brain Barrier - 0.7581 Caco-2 permeable - 0.7342 P-glycoprotein substrate Substrate 0.7464 P-glycoprotein inhibitor I Non-inhibitor 0.9204 P-glycoprotein inhibitor II Non-inhibitor 0.9222 Renal organic cation transporter Non-inhibitor 0.8783 CYP450 2C9 substrate Non-substrate 0.9002 CYP450 2D6 substrate Non-substrate 0.8025 CYP450 3A4 substrate Non-substrate 0.731 CYP450 1A2 substrate Non-inhibitor 0.8461 CYP450 2C9 inhibitor Non-inhibitor 0.8755 CYP450 2D6 inhibitor Non-inhibitor 0.9271 CYP450 2C19 inhibitor Non-inhibitor 0.8538 CYP450 3A4 inhibitor Non-inhibitor 0.8888 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9958 Ames test Non AMES toxic 0.6773 Carcinogenicity Non-carcinogens 0.9472 Biodegradation Not ready biodegradable 0.561 Rat acute toxicity 2.2102 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.8805 hERG inhibition (predictor II) Non-inhibitor 0.7963
- Mass Spec (NIST)
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Spectrum Spectrum Type Splash Key Predicted GC-MS Spectrum - GC-MS Predicted GC-MS Not Available
- This compound belongs to the class of organic compounds known as alpha amino acids. These are amino acids in which the amino group is attached to the carbon atom immediately adjacent to the carboxylate group (alpha carbon).
- Organic compounds
- Super Class
- Organic acids and derivatives
- Carboxylic acids and derivatives
- Sub Class
- Amino acids, peptides, and analogues
- Direct Parent
- Alpha amino acids
- Alternative Parents
- Tricarboxylic acids and derivatives / 1,3-aminoalcohols / Trialkylamines / Secondary alcohols / 1,2-aminoalcohols / Amino acids / Carboxylic acid salts / Polyols / Azacyclic compounds / Carboxylic acidsHydrocarbon derivatives / Organic oxides / Carbonyl compounds / Organic salts / Organic zwitterions / Organopnictogen compounds / Primary alcohols show 7 more
- Alpha-amino acid / Tricarboxylic acid or derivatives / 1,3-aminoalcohol / 1,2-aminoalcohol / Carboxylic acid salt / Amino acid / Secondary alcohol / Tertiary amine / Tertiary aliphatic amine / Carboxylic acidPolyol / Azacycle / Organoheterocyclic compound / Hydrocarbon derivative / Primary alcohol / Organic oxygen compound / Organooxygen compound / Organonitrogen compound / Organic nitrogen compound / Organic oxide / Carbonyl group / Amine / Organopnictogen compound / Alcohol / Organic salt / Organic zwitterion / Aliphatic heteromonocyclic compound show 17 more
- Molecular Framework
- Aliphatic heteromonocyclic compounds
- External Descriptors
- gadolinium coordination entity (CHEBI:68841)
Drug created on May 15, 2010 11:36 / Updated on November 14, 2018 12:54