Gadobutrol

Identification

Name
Gadobutrol
Accession Number
DB06703
Type
Small Molecule
Groups
Approved
Description

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.

Structure
Thumb
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
Active Moieties
NameKindUNIICASInChI Key
Gadolinium cation (3+)ionicAZV954TZ9N22541-19-1RJOJUSXNYCILHH-UHFFFAOYSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
GadavistInjection604.72 mg/1mLIntravenousBayer HealthCare Pharmaceuticals Inc.2011-03-14Not applicableUs
Gadovist 1.0Solution604.72 mgIntravenousBayer2004-01-30Not applicableCanada
International/Other Brands
Gadovist (Bayer Schering Pharma)
Categories
UNII
1BJ477IO2L
CAS number
770691-21-9
Weight
Average: 604.72
Monoisotopic: 605.13321
Chemical Formula
C18H31GdN4O9
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

Pharmacology

Indication

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
Pharmacodynamics

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.

Absorption

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.

Metabolism

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).

Clearance

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%.

Toxicity

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
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
No interactions found.
Food Interactions
  • Not affected by food.

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. [PubMed:23435930]
  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. [PubMed:23011188]
  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. [PubMed:18821778]
External Links
Human Metabolome Database
HMDB0015649
KEGG Drug
D07420
PubChem Compound
70678987
PubChem Substance
99443257
ChemSpider
28533281
ChEBI
68841
ChEMBL
CHEMBL2218860
PharmGKB
PA165958377
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Gadobutrol
ATC Codes
V08CA09 — Gadobutrol
AHFS Codes
  • 36:89.00* — Other Diagnostics
FDA label
Download (103 KB)
MSDS
Download (40.2 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0Not Yet RecruitingBasic ScienceBrain Tumor Adult1
1CompletedDiagnosticLeft Atrial Fibrosis1
1CompletedDiagnosticMagnetic Resonance Imaging (MRI)2
2CompletedDiagnosticBrain Diseases / Spinal Cord Diseases1
2CompletedDiagnosticMagnetic Resonance Imaging (MRI) / Myocardial Perfusion Imaging1
2RecruitingDiagnosticBrain Neoplasms, Malignant / Metastasis1
3CompletedDiagnosticCancer, Breast1
3CompletedDiagnosticCancer, Breast / Diagnostic Imaging1
3CompletedDiagnosticCarotid Stenosis1
3CompletedDiagnosticCentral Nervous System Diseases2
3CompletedDiagnosticCentral Nervous System Diseases / Diagnostic Imaging1
3CompletedDiagnosticCoronary Artery Disease2
3CompletedDiagnosticMagnetic Resonance Imaging (MRI)2
3CompletedDiagnosticMetastatic Brain Tumors1
3CompletedDiagnosticRenal Artery Obstruction1
3CompletedDiagnosticVascular Diseases1
3Enrolling by InvitationDiagnosticAdenocarcinoma, Prostate1
4CompletedDiagnosticBrain Diseases1
4CompletedDiagnosticBrain Lesions1
4CompletedDiagnosticNeoplastic CNS Lesions1
4CompletedDiagnosticPeripheral Arterial Disease (PAD)1
4CompletedDiagnosticPrimary Brain Tumors1
4CompletedTreatmentFibrosis / Impaired Renal Function1
4RecruitingDiagnosticDisseminated Sclerosis1
4RecruitingDiagnosticMagnetic Resonance Imaging (MRI)1
Not AvailableCompletedNot AvailableEpidemiologic Factors1
Not AvailableCompletedNot AvailableImage Enhancement / Magnetic Resonance Imaging (MRI)1
Not AvailableCompletedNot AvailableMagnetic Resonance Angiography / Magnetic Resonance Imaging (MRI)1
Not AvailableCompletedNot AvailableMagnetic Resonance Imaging (MRI)1
Not AvailableCompletedDiagnosticMalignant Neoplasm of Pancreas2
Not AvailableCompletedHealth Services ResearchRadiculopathy, Cervical1
Not AvailableNot Yet RecruitingOtherCoronary Artery Atherosclerosis1
Not AvailableRecruitingNot AvailableCoronary Artery Disease / Coronary Microvascular Disease1
Not AvailableTerminatedDiagnosticAdult Anaplastic (Malignant) Meningioma / Adult Anaplastic Astrocytoma / Adult Anaplastic Ependymoma / Adult Anaplastic Oligodendroglioma / Adult Brain Stem Glioma / Adult Choroid Plexus Neoplasm / Adult Diffuse Astrocytoma / Adult Ependymoblastoma / Adult Ependymoma / Adult Giant Cell Glioblastoma / Adult Glioblastoma / Adult Gliosarcoma / Adult Grade II Meningioma / Adult Medulloblastoma / Adult Mixed Glioma / Adult Oligodendroglioma / Adult Papillary Meningioma / Adult Pineal Gland Astrocytoma / Adult Pineoblastoma / Adult Primary Melanocytic Lesion of Meninges / Adult Supratentorial Primitive Neuroectodermal Tumor / Disseminated Sclerosis / Malignant Adult Intracranial Hemangiopericytoma / Metastatic Malignant Neoplasm in the Brain / Recurrent Adult Brain Neoplasm1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
InjectionIntravenous604.72 mg/1mL
SolutionIntravenous604.72 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US5980864No1996-11-092016-11-09Us

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-MSNot Available

Taxonomy

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
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 acid
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