Gadobutrol

Identification

Summary

Gadobutrol is a gadolinium-based contrast agent (GBCA) used with contrasted magnetic resonance imaging (MRI) to detect and visualize lesions and abnormal vascularity.

Brand Names
Gadavist, Gadovist
Generic Name
Gadobutrol
DrugBank Accession Number
DB06703
Background

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.1

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.1

Type
Small Molecule
Groups
Approved
Structure
Weight
Average: 604.72
Monoisotopic: 605.13321
Chemical Formula
C18H31GdN4O9
Synonyms
  • Gadobutrol
  • 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

Pharmacology

Indication

Gadobutrol is indicated for use with magnetic resonance imaging for the following diagnostic processes:6

  • 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
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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Diagnostic processArterial occlusive diseases of the supra-aortic arteries•••••••••••••••••• ••••••••• ••••••••••••••••••
Diagnostic processCns abnormal vascularity•••••••••••••••••• ••••••••• ••••••••••••••••••
Diagnostic processMyocardial perfusion imaging••••••••••••••••••••••••• •••••• ••••••• ••••••••••••••
Diagnostic processRenal artery occlusion•••••••••••••••••• ••••••••• ••••••••••••••••••
Diagnostic processMalignant breast disease••••••••••••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Gadobutrol leads to distinct shortenings of relaxation times even in low concentrations. At pH 7, 37°C and 1.5 T, the relaxivity (r1) - determined from the influence on the relaxation times (T1) of protons in plasma - is 5.2 L/(mmol·sec) and the relaxivity (r2) - determined from the influence on the relaxation times (T2) - is 6.1 L/(mmol·sec). These relaxivities display only slight dependence on the strength of the magnetic field.6

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).6

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.6

Absorption

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.6

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.6

Volume of distribution

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.4

Protein binding

No information is available on the protein binding of gadobutrol.

Metabolism

Gadobutrol is not metabolized.6

Route of elimination

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.6

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.6

Clearance

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.6

Adverse Effects
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Toxicity

GBCAs cross the placenta and result in fetal exposure and gadolinium retention. The human data on the association between GBCAs and adverse fetal outcomes are limited and inconclusive. In animal reproduction studies, although teratogenicity was not observed, embryo-lethality was observed in monkeys, rabbits, and rats receiving intravenous gadobutrol during organogenesis at doses 8 times and above the recommended human dose. Retardation of embryonal development was observed in rabbits and rats receiving intravenous gadobutrol during organogenesis at doses 8 and 12 times, respectively, the recommended human dose. Because of the potential risks of gadolinium to the fetus, use Gadavist only if imaging is essential during pregnancy and cannot be delayed.6

The maximum dose of gadobutrol tested in healthy volunteers, 1.5 mL/kg body weight (1.5 mmol/kg; 15 times the recommended dose), was tolerated in a manner similar to lower doses. Gadobutrol can be removed by hemodialysis [

No carcinogenicity studies of gadobutrol have been conducted.6

Gadobutrol was not mutagenic in in vitro reverse mutation tests in bacteria, in the HGPRT (hypoxanthine-guanine phosphoribosyl transferase) test using cultured Chinese hamster V79 cells, or in chromosome aberration tests in human peripheral blood lymphocytes, and was negative in an in vivo micronucleus test in mice after intravenous injection of 0.5 mmol/kg.6

Gadobutrol had no effect on fertility and general reproductive performance of male and female rats when given in doses 12.2 times the human equivalent dose (based on body surface area).6

Local intolerance reactions, including moderate irritation associated with infiltration of inflammatory cells was observed after paravenous administration to rabbits, suggesting the possibility of occurrence of local irritation if the contrast medium leaks around veins in a clinical setting.6

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
No interactions found.
Food Interactions
No interactions found.

Products

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Active Moieties
NameKindUNIICASInChI Key
Gadolinium cation (3+)ionicAZV954TZ9N22541-19-1RJOJUSXNYCILHH-UHFFFAOYSA-N
International/Other Brands
Gadovist (Bayer Schering Pharma)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
GadavistInjection604.72 mg/1mLIntravenousBayer HealthCare Pharmaceuticals Inc.2011-03-14Not applicableUS flag
Gadovist 1.0Solution604.72 mg / mLIntravenousBayer2004-01-30Not applicableCanada flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
GadobutrolInjection604.72 mg/1mLIntravenousSlate Run Pharmaceuticals, Llc2023-06-01Not applicableUS flag
GadobutrolInjection604.72 mg/1mLIntravenousFresenius Kabi USA, LLC2023-10-01Not applicableUS flag
GadobutrolInjection604.72 mg/1mLIntravenousSlate Run Pharmaceuticals, Llc2023-10-20Not applicableUS flag
GadobutrolInjection604.72 mg/1mLIntravenousFresenius Kabi USA, LLC2023-04-14Not applicableUS flag
GadobutrolInjection604.72 mg/1mLIntravenousFresenius Kabi USA, LLC2023-10-01Not applicableUS flag

Categories

ATC Codes
V08CA09 — Gadobutrol
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
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).
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
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 acids
show 7 more
Substituents
1,2-aminoalcohol / 1,3-aminoalcohol / Alcohol / Aliphatic heteromonocyclic compound / Alpha-amino acid / Amine / Amino acid / Azacycle / Carbonyl group / Carboxylic acid
show 17 more
Molecular Framework
Aliphatic heteromonocyclic compounds
External Descriptors
gadolinium coordination entity (CHEBI:68841)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
1BJ477IO2L
CAS number
770691-21-9
InChI Key
ZPDFIIGFYAHNSK-YYLIZZNMSA-K
InChI
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-;/m0./s1
IUPAC Name
4,7,10-tris(carboxymethyl)-1-[(2S,3R)-1,3,4-trihydroxybutan-2-yl]-1,4,7,10-tetraaza-13-gadolinatetracyclo[5.5.1.0^{4,13}.0^{10,13}]tridecane-1,4,7,10-tetraium-13-uide
SMILES
OC[C@H](O)[C@H](CO)[N+]12CC[N+]3(CC([O-])=O)CC[N+]4(CC([O-])=O)CC[N+](CC([O-])=O)(CC1)[Gd-]234

References

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
  1. 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. [Article]
  2. 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. [Article]
  3. 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. [Article]
  4. Hahn G, Sorge I, Gruhn B, Glutig K, Hirsch W, Bhargava R, Furtner J, Born M, Schroder C, Ahlstrom H, Kaiser S, Moritz JD, Kunze CW, Shroff M, Stokland E, Trnkova ZJ, Schultze-Mosgau M, Reif S, Bacher-Stier C, Mentzel HJ: Pharmacokinetics and safety of gadobutrol-enhanced magnetic resonance imaging in pediatric patients. Invest Radiol. 2009 Dec;44(12):776-83. doi: 10.1097/RLI.0b013e3181bfe2d2. [Article]
  5. FDA Approved Drug Products: Gadavist (gadobutrol) injection for intravenous administration [Link]
  6. FDA Approved Drug Products: GADAVIST (gadobutrol) injection, for intravenous use (Feb 2024) [Link]
Human Metabolome Database
HMDB0015649
KEGG Drug
D07420
PubChem Compound
70678987
PubChem Substance
99443257
ChemSpider
28533281
RxNav
84990
ChEBI
68841
ChEMBL
CHEMBL2218860
PharmGKB
PA165958377
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Gadobutrol
FDA label
Download (103 KB)
MSDS
Download (40.2 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedDiagnosticBrain Disorders1
4CompletedDiagnosticBrain Lesions1
4CompletedDiagnosticMagnetic Resonance Imaging (MRI)1
4CompletedDiagnosticNeoplastic CNS Lesions1
4CompletedDiagnosticPeripheral Arterial Disease (PAD)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
InjectionIntravenous604.72 mg/1mL
Injection, solutionParenteral
Injection, solution
InjectionIntravenous
InjectionIntravenous0.5 MMOL/ML
InjectionIntravenous1 MMOL/ML
Injection, solutionIntravenous0.5 MMOL/ML
Injection, solutionIntravenous1 MMOL/ML
Injection, solutionParenteral1 MMOL/ML
Injection, solutionParenteral1.0 MMOL/ML
SolutionIntravenous604.72 mg/1ml
SolutionIntravenous604.72 mg / mL
SolutionIntravenous604.72 mg/ml
Injection, solutionIntravenous
InjectionIntravenous604.72 mg
InjectionIntravenous604.720 mg
SolutionIntravenous1 mmol
Injection, solution1.0 mmol/ml
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US5980864No1999-11-092016-11-09US flag

Properties

State
Liquid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0496 mg/mLALOGPS
logP0.35ALOGPS
logP-4.6Chemaxon
logS-4.2ALOGPS
pKa (Strongest Acidic)0.99Chemaxon
pKa (Strongest Basic)-3Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count9Chemaxon
Hydrogen Donor Count3Chemaxon
Polar Surface Area181.08 Å2Chemaxon
Rotatable Bond Count10Chemaxon
Refractivity143.47 m3·mol-1Chemaxon
Polarizability45.39 Å3Chemaxon
Number of Rings4Chemaxon
Bioavailability1Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption-0.9703
Blood Brain Barrier-0.7581
Caco-2 permeable-0.7342
P-glycoprotein substrateSubstrate0.7464
P-glycoprotein inhibitor INon-inhibitor0.9204
P-glycoprotein inhibitor IINon-inhibitor0.9222
Renal organic cation transporterNon-inhibitor0.8783
CYP450 2C9 substrateNon-substrate0.9002
CYP450 2D6 substrateNon-substrate0.8025
CYP450 3A4 substrateNon-substrate0.731
CYP450 1A2 substrateNon-inhibitor0.8461
CYP450 2C9 inhibitorNon-inhibitor0.8755
CYP450 2D6 inhibitorNon-inhibitor0.9271
CYP450 2C19 inhibitorNon-inhibitor0.8538
CYP450 3A4 inhibitorNon-inhibitor0.8888
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9958
Ames testNon AMES toxic0.6773
CarcinogenicityNon-carcinogens0.9472
BiodegradationNot ready biodegradable0.561
Rat acute toxicity2.2102 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8805
hERG inhibition (predictor II)Non-inhibitor0.7963
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Download (21.2 KB)
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSsplash10-08gi-4109200000-e2cb64efbe4b4b47d094
Chromatographic Properties
Collision Cross Sections (CCS)
Not Available

Drug created at May 15, 2010 17:36 / Updated at May 29, 2024 19:09