Gadobenic acid

Identification

Summary

Gadobenic acid is a gadolinium compound used as a contrast agent in MRIs.

Brand Names
Multihance
Generic Name
Gadobenic acid
DrugBank Accession Number
DB00743
Background

Gadobenic acid (in the form of gadobenate dimeglumine) is an MRI contrast agent used primarily for MR imaging of the liver. It can also be used for visualizing the CNS and heart. In contrast to conventional extracellular fluid contrast agents, gadobenate dimeglumine is characterized by a weak and transient binding capacity to serum proteins. This binding leads to an increased relaxivity of gadobenate dimeglumine and, consequently, to a considerably increased signal intensity over that of other agents.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 667.73
Monoisotopic: 668.09649
Chemical Formula
C22H28GdN3O11
Synonyms
  • Acide gadobenique
  • Acido gadobenico
  • Acidum gadobenicum
  • Gadobenate
  • Gadobenic acid
  • Gadobensäure
External IDs
  • B 19036
  • B 19036/7

Pharmacology

Indication

Gadobenate Dimeglumine is an MRI contrast agent used primarily for MR imaging of the liver. It can also be used for MRI of the heart, as well as and central nervous system in adults to visualize lesions with abnormal brain vascularity or abnormalities in the blood brain barrier, the brain, spine, or other associated tissues.

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Gadobenate dimeglumine shares the pharmacokinetic properties of the ECF contrast agent gadopentetate dimeglumine; however, gadobenate differs in that is also selectively taken-up by hepatocytes and excreted via the bile (up to 5% of dose). The elimination half-life of gadobenate dimeglumine is approximately 1 hour. It is not metabolized.

Mechanism of action

Based on the behavior of protons when placed in a strong magnetic field, which is interpreted and transformed into images by magnetic resonance (MR) instruments. Paramagnetic agents have unpaired electrons that generate a magnetic field about 700 times larger than the proton's field, thus disturbing the proton's local magnetic field. When the local magnetic field around a proton is disturbed, its relaxation process is altered. MR images are based on proton density and proton relaxation dynamics. MR instruments can record 2 different relaxation processes, the T1 (spin-lattice or longitudinal relaxation time) and the T2 (spin-spin or transverse relaxation time). In magnetic resonance imaging (MRI), visualization of normal and pathological brain tissue depends in part on variations in the radiofrequency signal intensity that occur with changes in proton density, alteration of the T1, and variation in the T2. When placed in a magnetic field, Gadobenate Dimeglumine shortens both the T1 and the T2 relaxation times in tissues where it accumulates. At clinical doses, Gadobenate Dimeglumine primarily affects the T1 relaxation time, thus producing an increase in signal intensity. Gadobenate Dimeglumine does not cross the intact blood-brain barrier; therefore, it does not accumulate in normal brain tissue or in central nervous system (CNS) lesions that have not caused an abnormal blood-brain barrier (e.g., cysts, mature post-operative scars).

Absorption

Not Available

Volume of distribution

Not Available

Protein binding

Plasma protein binding is low, weak, and transient.

Metabolism

Not metabolized.

Route of elimination

Gadobenate ion is eliminated predominately via the kidneys, with 78% to 96% of an administered dose recovered in the urine.

Half-life

1 hour

Clearance
  • 0.093 +/- 0.010 L/hr/kg [healthy male subjects receiving 3 single-dose IV administration with doses from 0.005-0.4 mmol/kg]
Adverse Effects
Adverseeffects
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Toxicity

Gadolinium-based radiocontrast agents like gadobenate dimeglumine are cytotoxic to renal cells. The toxic effects include apoptosis, cellular energy failure, disruption of calcium homeostasis, and disturbance of tubular cell polarity, and are thought to be linked to oxidative stress.

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
AbacavirGadobenic acid may decrease the excretion rate of Abacavir which could result in a higher serum level.
AceclofenacAceclofenac may decrease the excretion rate of Gadobenic acid which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Gadobenic acid which could result in a higher serum level.
AcetaminophenAcetaminophen may decrease the excretion rate of Gadobenic acid which could result in a higher serum level.
AcetazolamideAcetazolamide may increase the excretion rate of Gadobenic acid which could result in a lower serum level and potentially a reduction in efficacy.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Gadobenic acid which could result in a higher serum level.
AclidiniumGadobenic acid may decrease the excretion rate of Aclidinium which could result in a higher serum level.
AcrivastineThe risk or severity of QTc prolongation can be increased when Acrivastine is combined with Gadobenic acid.
AcyclovirAcyclovir may decrease the excretion rate of Gadobenic acid which could result in a higher serum level.
Adefovir dipivoxilAdefovir dipivoxil may decrease the excretion rate of Gadobenic acid which could result in a higher serum level.
Interactions
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Food Interactions
No interactions found.

Products

Products2
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Product Ingredients
IngredientUNIICASInChI Key
Gadobenate dimeglumine3Q6PPC19PO127000-20-8OCDAWJYGVOLXGZ-VPVMAENOSA-K
Active Moieties
NameKindUNIICASInChI Key
Gadolinium cation (3+)ionicAZV954TZ9N22541-19-1RJOJUSXNYCILHH-UHFFFAOYSA-N
International/Other Brands
Multihance Multipack (Bracco)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
MultiHanceInjection, solution529 mg/1mLIntravenousBracco Diagnostics Inc2004-11-23Not applicableUS flag
MultiHanceSolution529 mg / mLIntravenousBracco Imaging S.P.A.2004-10-28Not applicableCanada flag
MultiHanceInjection, solution529 mg/1mLIntravenousBracco Diagnostics Inc2004-11-23Not applicableUS flag

Categories

ATC Codes
V08CA08 — Gadobenic acid
Drug Categories
Classification
Not classified
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
15G12L5X8K
CAS number
113662-23-0
InChI Key
MXZROTBGJUUXID-UHFFFAOYSA-K
InChI
InChI=1S/C22H31N3O11.Gd/c26-18(27)10-23(6-7-24(11-19(28)29)12-20(30)31)8-9-25(13-21(32)33)17(22(34)35)15-36-14-16-4-2-1-3-5-16;/h1-5,17H,6-15H2,(H,26,27)(H,28,29)(H,30,31)(H,32,33)(H,34,35);/q;+3/p-3
IUPAC Name
gadolinium(3+) ion 4-carboxy-8,11-bis(carboxylatomethyl)-5-(carboxymethyl)-1-phenyl-2-oxa-5,8,11-triazatridecan-13-oate
SMILES
[Gd+3].OC(=O)CN(CCN(CCN(CC([O-])=O)CC([O-])=O)CC([O-])=O)C(COCC1=CC=CC=C1)C(O)=O

References

Synthesis Reference

Pier Lucio Anelli, Pierfrancesco Morisini, Silvia Ceragioli, Fulvio Uggeri, Luciano Lattuada, Roberta Fretta, Aurelia Ferrigato, "Process for the Preparation of Gadobenate Dimeglumine Complex in a Solid Form." U.S. Patent US20120232151, issued September 13, 2012.

US20120232151
General References
  1. de Haen C, Cabrini M, Akhnana L, Ratti D, Calabi L, Gozzini L: Gadobenate dimeglumine 0.5 M solution for injection (MultiHance) pharmaceutical formulation and physicochemical properties of a new magnetic resonance imaging contrast medium. J Comput Assist Tomogr. 1999 Nov;23 Suppl 1:S161-8. [Article]
  2. Morana G, Salviato E, Guarise A: Contrast agents for hepatic MRI. Cancer Imaging. 2007 Oct 1;7 Spec No A:S24-7. [Article]
  3. Vogl TJ, Pegios W, McMahon C, Balzer J, Waitzinger J, Pirovano G, Lissner J: Gadobenate dimeglumine--a new contrast agent for MR imaging: preliminary evaluation in healthy volunteers. AJR Am J Roentgenol. 1992 Apr;158(4):887-92. [Article]
  4. Kirchin MA, Pirovano GP, Spinazzi A: Gadobenate dimeglumine (Gd-BOPTA). An overview. Invest Radiol. 1998 Nov;33(11):798-809. [Article]
  5. Clement O, Siauve N, Cuenod CA, Vuillemin-Bodaghi V, Leconte I, Frija G: Mechanisms of action of liver contrast agents: impact for clinical use. J Comput Assist Tomogr. 1999 Nov;23 Suppl 1:S45-52. [Article]
  6. Sweetman, Sean C. (2009). Contrast Media. In Martindale : The Complete Drug Reference, 36th Edition 2 Volume Set (36th ed., pp. 1478). Pharmaceutical Press. [ISBN:978-0-85369-840-1]
KEGG Drug
D08018
PubChem Compound
131704172
PubChem Substance
46506805
ChemSpider
94843
RxNav
692620
ChEMBL
CHEMBL1200571
Therapeutic Targets Database
DAP001225
PharmGKB
PA164745426
Wikipedia
Gadobenic_acid
FDA label
Download (247 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedNot AvailableBrain Pathology1
4CompletedDiagnosticBrain Diseases1
4CompletedDiagnosticBrain Lesions1
4CompletedDiagnosticNeoplasms, Brain1
4RecruitingDiagnosticColorectal Carcinoma (CRC) / Hepatic Metastases / Oligometastatic Disease1
4RecruitingOtherCognitive Functioning / Contrast Medium / Motor Function1
3CompletedDiagnosticBreast Cancer1
3CompletedDiagnosticCarotid, Aortic, Renal or Peripheral Artery Disease1
3CompletedDiagnosticPeripheral Vascular Disease Patient1
3CompletedDiagnosticSteno-Occlusive Disease1

Pharmacoeconomics

Manufacturers
  • Bracco diagnostics inc
Packagers
  • Bracco Diagnostics Inc.
  • Nycomed Inc.
  • Patheon Inc.
Dosage Forms
FormRouteStrength
InjectionIntravenous
Injection, solutionIntravenous
Injection, solutionIntravenous529 mg/1mL
SolutionIntravenous334 mg/1ml
SolutionIntravenous529 mg / mL
Injection, solutionParenteral
SolutionIntravenous
Prices
Unit descriptionCostUnit
Multihance 529 mg/ml vial6.87USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US4916246No1990-04-102012-04-10US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.768 mg/mLALOGPS
logP0.92ALOGPS
logP-4.1ChemAxon
logS-3ALOGPS
pKa (Strongest Acidic)0.085ChemAxon
pKa (Strongest Basic)9.58ChemAxon
Physiological Charge-3ChemAxon
Hydrogen Acceptor Count14ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area213.94 Å2ChemAxon
Rotatable Bond Count20ChemAxon
Refractivity154.36 m3·mol-1ChemAxon
Polarizability48.32 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption-0.9749
Blood Brain Barrier-0.9391
Caco-2 permeable-0.691
P-glycoprotein substrateSubstrate0.8261
P-glycoprotein inhibitor INon-inhibitor0.7702
P-glycoprotein inhibitor IINon-inhibitor0.7288
Renal organic cation transporterNon-inhibitor0.8635
CYP450 2C9 substrateNon-substrate0.8598
CYP450 2D6 substrateNon-substrate0.8006
CYP450 3A4 substrateNon-substrate0.6356
CYP450 1A2 substrateNon-inhibitor0.8637
CYP450 2C9 inhibitorNon-inhibitor0.8597
CYP450 2D6 inhibitorNon-inhibitor0.8675
CYP450 2C19 inhibitorNon-inhibitor0.8851
CYP450 3A4 inhibitorNon-inhibitor0.9349
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9905
Ames testNon AMES toxic0.8062
CarcinogenicityNon-carcinogens0.9179
BiodegradationNot ready biodegradable0.8088
Rat acute toxicity2.3557 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8499
hERG inhibition (predictor II)Non-inhibitor0.6371
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. Port M, Corot C, Violas X, Robert P, Raynal I, Gagneur G: How to compare the efficiency of albumin-bound and nonalbumin-bound contrast agents in vivo: the concept of dynamic relaxivity. Invest Radiol. 2005 Sep;40(9):565-73. [Article]
  2. Wendland MF, Saeed M, Lauerma K, Derugin N, Mintorovitch J, Cavagna FM, Higgins CB: Alterations in T1 of normal and reperfused infarcted myocardium after Gd-BOPTA versus GD-DTPA on inversion recovery EPI. Magn Reson Med. 1997 Mar;37(3):448-56. [Article]
  3. Cavagna FM, Maggioni F, Castelli PM, Dapra M, Imperatori LG, Lorusso V, Jenkins BG: Gadolinium chelates with weak binding to serum proteins. A new class of high-efficiency, general purpose contrast agents for magnetic resonance imaging. Invest Radiol. 1997 Dec;32(12):780-96. [Article]
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]

Drug created on June 13, 2005 13:24 / Updated on September 19, 2021 19:53