Gadoteric acid

Identification

Summary

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

Brand Names
Dotarem
Generic Name
Gadoteric acid
DrugBank Accession Number
DB09132
Background

Gadoteric acid, commonly used in the salt form gadoterate meglumine, is a macrocyclic, ionic gadolinium-based contrast agent (GBCA).1 It is composed of the organic acid DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) used for its chelating properties, and gadolinium (Gd3+).2 Gadoterate meglumine has one of the highest thermodynamic stability, apparent stability, and kinetic stability, partly due to its macrocyclic structure, and thus has a more favorable safety profile due to a decreased tendency of gadolinium dechelation.3,4

Gadoterate is approved by the FDA under the brand name DOTAREM on 20th March 2013 for intravenous uses with magnetic resonance imaging (MRI) in the brain (intracranial), spine, and associated tissues in adult and pediatric patients (2 years of age and older) to detect and visualize areas with disruption of the blood-brain barrier (BBB) and/or abnormal vascularity.7

Type
Small Molecule
Groups
Approved
Structure
Weight
Average: 558.65
Monoisotopic: 559.09135
Chemical Formula
C16H25GdN4O8
Synonyms
  • [2,2',2'',2'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl-κ4N1,N4,N7,N10)tetraacetato(3−)]gadolinium
  • DOTA-Gd
  • Gadoterate
  • Gadoteric acid
  • Gd-DOTA

Pharmacology

Indication

Gadoteric acid is indicated for intravenous use with magnetic resonance imaging (MRI) in the brain (intracranial), spine, and associated tissues in adult and pediatric patients (including term neonates) to detect and visualize areas with disruption of the blood-brain barrier (BBB) and/or abnormal vascularity.5

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Diagnostic agentCns abnormal vascularity•••••••••••••••••• ••••••••• ••••••••••••••••••
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Pharmacodynamics

Gadoterate affects proton relaxation times and consequently the MR signal, and the contrast obtained is characterized by the relaxivity of the gadoterate molecule. The relaxivity values for gadoterate are similar across the spectrum of magnetic field strengths used in clinical MRI (0.2-1.5 T). Disruption of the blood-brain barrier or abnormal vascularity allows the distribution of gadoterate in lesions such as neoplasms, abscesses, and infarcts.5

Mechanism of action

Gadoterate is a paramagnetic molecule that develops a magnetic moment when placed in a magnetic field. The magnetic moment enhances the relaxation rates of water protons in its vicinity, leading to an increase in signal intensity (brightness) of tissues.5

In magnetic resonance imaging (MRI), visualization of normal and pathological tissue depends in part on variations in the radiofrequency signal intensity that occur with differences in proton density, spin-lattice or longitudinal relaxation times (T1), and differences in the spin-spin or transverse relaxation time (T2). When placed in a magnetic field, gadoterate shortens the T1 and T2 relaxation times in target tissues. At recommended doses, the effect is observed with greatest sensitivity in the T1-weighted sequences.5

Absorption

Within the studied dose range (0.1 to 0.3 mmol/kg), the kinetics of total gadolinium appear to be linear.5

Following the administration of 0.1 mmol/kg of gadoterate meglumine in healthy volunteers, the Cmax, Tmax, AUC0-t, and AUC0-∞ were measured to be 799.03 (192.63) µmol/L, 5.00 (0.10-10.00) min, 953.51 (76.22) µmolh/L, and 970.72 (73.34) µmolh/L for female and 836.85 (451.02) µmol/L, 5.00 (0.11-10.00) min, 1038.74 (240.46) µmolh/L, and 1061.16 (239.24) µmolh/L for male subjects respectively.6

Volume of distribution

The volume of distribution at steady state of total gadolinium in healthy subjects is 179 ± 26 and 211 ± 35 mL/kg in female and male subjects respectively, roughly equivalent to that of extracellular water. The extent of blood cell partitioning of gadoterate is not known.5

Protein binding

Gadoterate does not undergo protein binding in vitro.5

Metabolism

Gadoterate is not known to be metabolized.5

Route of elimination

Following a 0.1 mmol/kg dose of gadoterate, total gadolinium is excreted primarily in the urine with 72.9 ± 17.0% and 85.4 ± 9.7% (mean ± SD) eliminated within 48 hours, in female and male subjects, respectively. Similar values were achieved after a cumulative dose of 0.3 mmol/kg (0.1 + 0.2 mmol/kg, 20 minutes later), with 85.5 ± 13.2% and 92.0 ± 12.0% recovered in urine within 48 hrs in female and male subjects respectively.5

Half-life

Following an intravenously administered 0.1 mmol/kg, gadoterate demonstrates a mean elimination half-life of about 1.4 ± 0.2 hr and 2.0 ± 0.7 hr in female and male subjects, respectively.L49911]

Clearance

In healthy subjects, the renal and total clearance rates of total gadolinium are comparable (1.27 ± 0.32 and 1.74 ± 0.12 mL/min/kg in females; and 1.40 ± 0.31 and 1.64 ± 0.35 mL/min/kg in males, respectively) indicating that the drug is primarily cleared through the kidneys.5

Adverse Effects
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Toxicity

GBCAs cross the human 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, there were no adverse developmental effects observed in rats or rabbits with intravenous administration of gadoterate meglumine during organogenesis at doses of 16 and 10 times, respectively, the recommended human dose. Because of the potential risks of gadolinium to the fetus, use gadoterate only if imaging is essential during pregnancy and cannot be delayed.5

Gadoterate administered to healthy volunteers and to adult patients at cumulative doses up to 0.3 mmol/kg was tolerated in a manner similar to lower doses. Adverse reactions to overdosage with gadoterate have not been reported. Gadoterate can be removed from the body by hemodialysis.5

Long-term animal studies have not been performed to evaluate the carcinogenic potential of gadoterate meglumine.5

Gadoterate meglumine did not demonstrate mutagenic potential in in vitro bacterial reverse mutation assays (Ames test) using Salmonella typhimurium, in an in vitro chromosome aberration assay in Chinese hamster ovary cells, in an in vitro gene mutation assay in Chinese hamster lung cells, nor in an in vivo mouse micronucleus assay.5

No impairment of male or female fertility and reproductive performance were observed in rats after intravenous administration of gadoterate meglumine at the maximum tested dose of 10 mmol/kg/day (16 times the maximum human dose based on surface area), given during more than 9 weeks in males and more than 4 weeks in females. Sperm counts and sperm motility were not adversely affected by treatment with the drug.5

Local intolerance reactions, including moderate irritation associated with infiltration of inflammatory cells were observed after perivenous injection in rabbits suggesting the possibility of local irritation if the contrast medium leaks around the veins in a clinical setting.

Toxicity of gadoterate meglumine was evaluated in neonatal and juvenile (pre- and post-weaning) rats following a single or repeated intravenous administration at doses 1, 2, and 4 times the MHD based on BSA. Gadoterate meglumine was well tolerated at all dose levels tested and had no effect on growth, pre-weaning development, behavior, or sexual maturation.

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.
DrugInteraction
AbacavirAbacavir may decrease the excretion rate of Gadoteric acid which could result in a higher serum level.
AceclofenacAceclofenac may decrease the excretion rate of Gadoteric acid which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Gadoteric acid which could result in a higher serum level.
AcetaminophenAcetaminophen may decrease the excretion rate of Gadoteric acid which could result in a higher serum level.
AcetazolamideAcetazolamide may increase the excretion rate of Gadoteric acid which could result in a lower serum level and potentially a reduction in efficacy.
Food Interactions
No interactions found.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Gadoterate meglumineL0ND3981AG92943-93-6RYHQMKVRYNEBNJ-BMWGJIJESA-K
Active Moieties
NameKindUNIICASInChI Key
Gadolinium cation (3+)ionicAZV954TZ9N22541-19-1RJOJUSXNYCILHH-UHFFFAOYSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
DotaremInjection376.9 mg/1mLIntravenousGuerbet LLC2013-03-20Not applicableUS flag
DotaremInjection376.9 mg/1mLIntravenousGuerbet LLC2013-03-20Not applicableUS flag
DotaremSolution376.9 mg / mLIntravenousGuerbet2017-09-22Not applicableCanada flag
DotaremInjection376.9 mg/1mLIntravenousGuerbet LLC2019-09-18Not applicableUS flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ClariscanInjection, solution376.9 mg/1mLIntravenousGe Healthcare2019-11-01Not applicableUS flag
Gadoterate MeglumineInjection376.9 mg/1mLIntravenousFresenius Kabi USA, LLC2022-06-20Not applicableUS flag
Gadoterate MeglumineInjection376.9 mg/1mLIntravenousFresenius Kabi USA, LLC2022-06-20Not applicableUS flag
Gadoterate MeglumineInjection376.9 mg/1mLIntravenousFresenius Kabi USA, LLC2022-06-20Not applicableUS flag
Gadoterate MeglumineInjection376.9 mg/1mLIntravenousFresenius Kabi USA, LLC2022-06-20Not applicableUS flag

Categories

ATC Codes
V08CA02 — Gadoteric acid
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as tetracarboxylic acids and derivatives. These are carboxylic acids containing exactly four carboxyl groups.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Tetracarboxylic acids and derivatives
Direct Parent
Tetracarboxylic acids and derivatives
Alternative Parents
Alpha amino acids / Trialkylamines / Carboxylic acid salts / Amino acids / Carboxylic acids / Azacyclic compounds / Organopnictogen compounds / Organic zwitterions / Organic salts / Organic oxides
show 2 more
Substituents
Aliphatic heteromonocyclic compound / Alpha-amino acid / Alpha-amino acid or derivatives / Amine / Amino acid / Amino acid or derivatives / Azacycle / Carbonyl group / Carboxylic acid / Carboxylic acid salt
show 13 more
Molecular Framework
Aliphatic heteromonocyclic compounds
External Descriptors
gadolinium coordination entity (CHEBI:73732)
Affected organisms
Not Available

Chemical Identifiers

UNII
QVF9Y6955W
CAS number
72573-82-1
InChI Key
GFSTXYOTEVLASN-UHFFFAOYSA-K
InChI
InChI=1S/C16H28N4O8.Gd/c21-13(22)9-17-1-2-18(10-14(23)24)5-6-20(12-16(27)28)8-7-19(4-3-17)11-15(25)26;/h1-12H2,(H,21,22)(H,23,24)(H,25,26)(H,27,28);/q;+3/p-3
IUPAC Name
gadolinium(3+) ion 2-[4,7-bis(carboxylatomethyl)-10-(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]acetate
SMILES
[Gd+3].OC(=O)CN1CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC1

References

General References
  1. Fallenberg EM, Renz DM, Karle B, Schwenke C, Ingod-Heppner B, Reles A, Engelken FJ, Huppertz A, Hamm B, Taupitz M: Intraindividual, randomized comparison of the macrocyclic contrast agents gadobutrol and gadoterate meglumine in breast magnetic resonance imaging. Eur Radiol. 2015 Mar;25(3):837-49. doi: 10.1007/s00330-014-3426-0. Epub 2014 Sep 25. [Article]
  2. Xiao Y, Xue R, You T, Li X, Pei F, Wang X, Lei H: Gadolinium-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid conjugate of arabinogalactan as a potential liver-targeting magnetic resonance imaging contrast agent. Carbohydr Res. 2014 Aug 18;395:9-14. doi: 10.1016/j.carres.2014.05.022. Epub 2014 Jun 6. [Article]
  3. Ishiguchi T, Takahashi S: Safety of gadoterate meglumine (Gd-DOTA) as a contrast agent for magnetic resonance imaging: results of a post-marketing surveillance study in Japan. Drugs R D. 2010;10(3):133-45. doi: 10.2165/11539140-000000000-00000. [Article]
  4. Robert P, Violas X, Grand S, Lehericy S, Idee JM, Ballet S, Corot C: Linear Gadolinium-Based Contrast Agents Are Associated With Brain Gadolinium Retention in Healthy Rats. Invest Radiol. 2016 Feb;51(2):73-82. doi: 10.1097/RLI.0000000000000241. [Article]
  5. FDA Approved Drug Products: DOTAREM® (gadoterate meglumine) Injection for intravenous us [Link]
  6. GADOTERATE CLINICAL PHARMACOLOGY NDA REVIEW [Link]
  7. Gadoterate Clinical Pharmacology Review [Link]
KEGG Drug
D08007
PubChem Compound
158536
PubChem Substance
310265047
ChemSpider
139460
ChEBI
73732
ChEMBL
CHEMBL3833326
Drugs.com
Drugs.com Drug Page
Wikipedia
Gadoteric_acid
FDA label
Download (3.85 MB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedNot AvailableArterial Occlusive Diseases1
4CompletedDiagnosticBrain Disorders1
4CompletedDiagnosticCoronary Artery Atherosclerosis / Type 2 Diabetes Mellitus1
4CompletedDiagnosticImpaired Renal Function1
4CompletedDiagnosticMagnetic Resonance Imaging (MRI)2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solutionIntra-articular1.397 mg/ml
Injection, solutionIntravenous376.9 mg/1mL
InjectionIntravenous0.5 mmol/mL
Injection, solutionIntravenous279.3 mg/ml
SolutionIntravenous279.3 mg
Injection, solutionIntramuscular0.5 mmol/ml
Injection, solutionIntramuscular
SolutionIntravenous0.5 mmol/ml
InjectionIntravenous376.9 mg/1mL
Injection, solution
Injection, solution0.5 MMOL/ML
Injection, solution00025 MMOL/ML
Injection, solutionIntravenous
SolutionIntravenous376.9 mg / mL
SolutionIntravenous377 mg/1ml
Injection, solutionParenteral279.32 mg/ml
Injection, solutionIntravenous0.5 mmol/ml
Injection, solutionIntravenous27.932 g/100ml
InjectionIntravenous27.932 g/100ml
Injection, solutionIntravenous279.32 mg/ml
Injection, solutionParenteral0.5 mmol/ml
Injection, solution377 mg/1ml
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility12.8 mg/mLALOGPS
logP0.23ALOGPS
logP-7.7Chemaxon
logS-1.7ALOGPS
pKa (Strongest Acidic)0.47Chemaxon
pKa (Strongest Basic)10.08Chemaxon
Physiological Charge-2Chemaxon
Hydrogen Acceptor Count12Chemaxon
Hydrogen Donor Count1Chemaxon
Polar Surface Area170.65 Å2Chemaxon
Rotatable Bond Count8Chemaxon
Refractivity128.93 m3·mol-1Chemaxon
Polarizability38.15 Å3Chemaxon
Number of Rings1Chemaxon
Bioavailability0Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSsplash10-052b-6019000000-3ef5221af748627b46a8
Chromatographic Properties
Collision Cross Sections (CCS)
Not Available

Drug created at September 29, 2015 19:58 / Updated at April 14, 2024 23:44