Gadobenic acid

Identification

Summary

Gadobenic 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
Multihance
Generic Name
Gadobenic acid
DrugBank Accession Number
DB00743
Background

Gadobenic acid, usually available in the salt form gadobenate dimeglumine, is a linear MRI gadolinium-based contrast agent (GBCA) used primarily for MR imaging of the liver.9 It differs from other GBCAs due to the benzene ring that confers weak protein binding, thus leading to an increased R1 and R2 relaxivity.8 As gadobenate dimeglumine is specifically taken up by hepatocytes and excreted through the biliary system, it is a useful contrast agent for liver MRI.3

Gadobenate dimeglumine was approved by the FDA in November 2004 under the brand name MultiHance.8

Type
Small Molecule
Groups
Approved, Investigational
Structure
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 indicated for use in magnetic resonance imaging (MRI) of the central nervous system in adult and pediatric patients in order to visualize lesions with abnormal blood-brain barrier or abnormal vascularity of the brain, spine, and associated tissues.11 It is also indicated for use in magnetic resonance angiography (MRA) to evaluate adults with known or suspected renal or aorto-ilio-femoral occlusive vascular disease.11

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Diagnostic agentAortoiliac occlusive disease•••••••••••••••••• ••••••••• ••••••••••••••••••• ••••••••
Diagnostic agentCns abnormal vascularity•••••••••••••••••• ••••••••• ••••••••••••••••••• ••••••••
Diagnostic agentFemoral artery occlusion•••••••••••••••••• ••••••••• ••••••••••••••••••• ••••••••
Diagnostic agentFemoral vein occlusion•••••••••••••••••• ••••••••• ••••••••••••••••••• ••••••••
Diagnostic agentRenal artery occlusion•••••••••••••••••• ••••••••• ••••••••••••••••••• ••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Unlike other paramagnetic contrast agents, gadobenate dimeglumine demonstrates weak and transient interactions with serum proteins that cause slowing in the molecular tumbling dynamics, resulting in strong increases in relaxivity in solutions containing serum proteins. The improved relaxation effect can contribute to increased contrast-to-noise ratio and lesion-to-brain ratio, which may improve visualization.12

Disruption of the blood-brain barrier or abnormal vascularity allows enhancement by gadobenate dimeglumine of lesions such as neoplasms, abscesses, and infarcts. Uptake of gadobenate dimeglumine into hepatocytes has been demonstrated.12

Mechanism of action

Gadobenate dimeglumine is a paramagnetic agent and, as such, develops a magnetic moment when placed in a magnetic field. The large magnetic moment produced by the paramagnetic agent results in a large local magnetic field, which can enhance the relaxation rates of water protons in its vicinity leading to an increase of signal intensity (brightness) of tissue.12

In magnetic resonance imaging (MRI), visualization of normal and pathological tissue depends in part on variations in the radiofrequency signal intensity that occur with 1) differences in proton density; 2) differences of the spin-lattice or longitudinal relaxation times (T1); and 3) differences in the spin-spin or transverse relaxation time (T2). When placed in a magnetic field, gadobenate dimeglumine decreases the T1 and T2 relaxation time in target tissues. At recommended doses, the effect is observed with the greatest sensitivity in the T1-weighted sequences.12

Absorption

Three single-dose intravenous studies were conducted in 32 healthy male subjects to assess the pharmacokinetics of gadobenate dimeglumine. The doses administered in these studies ranged from 0.005 to 0.4 mmol/kg. Upon injection, the meglumine salt is completely dissociated from the gadobenate dimeglumine complex. Thus, the pharmacokinetics is based on the assay of gadobenate ion, the MRI contrast effective ion in gadobenate dimeglumine. Data for plasma concentration and area under the curve demonstrated linear dependence on the administered dose. The pharmacokinetics of gadobenate ion following intravenous administration can be best described using a two-compartment model.12

A population pharmacokinetic analysis incorporated data from 25 healthy subjects (14 males and 11 females) and 15 subjects undergoing MR imaging of the central nervous system (7 males and 8 females) between ages of 2 and 16 years. The subjects received a single intravenous dose of 0.1 mmol/kg of gadobenate dimeglumine. The geometric mean Cmax was 62.3 µg/mL (n=16) in children 2 to 5 years of age, and 64.2 µg/mL (n=24) in children older than 5 years. The geometric mean AUC0-∞ was 77.9 μg⋅h/mL in children 2-5 years of age (n=16) and 82.6 μg⋅h/mL in children older than 5 years (n=24). The geometric mean half-life was 1.2 hours in children 2 to 5 years of age and 0.93 hours in children older than 5 years. There was no significant gender-related difference in the pharmacokinetic parameters in the pediatric patients. Pharmacokinetic simulations indicate similar AUC and Cmax values for gadobenate dimeglumine in pediatric subjects less than 2 years when compared to those reported for adults; no age-based dose adjustment is necessary for this pediatric population.12

Volume of distribution

The volume of distribution of the central compartment ranged from 0.074 ± 0.017 to 0.158 ± 0.038 L/kg, and estimates of volume of distribution by area ranged from 0.170 ± 0.016 to 0.282 ± 0.079 L/kg.12

Protein binding

Although in vitro studies showed no appreciable binding of gadobenate ion to human serum proteins, in vivo studies have demonstrated a weak affinity binding of gadobenate to albumin.6,7,12

Metabolism

There was no detectable biotransformation of gadobenate ion. Dissociation of gadobenate ion in vivo has been shown to be minimal, with less than 1% of the free chelating agent being recovered alone in feces.12

Route of elimination

Gadobenate ion is eliminated predominately via the kidneys, with 78% to 96% of an administered dose recovered in the urine. A small percentage of the administered dose (0.6% to 4%) is eliminated via the biliary route and recovered in feces.12

Half-life

Gadobenate ion has a rapid distribution half-life (reported as mean ± SD) of 0.084 ± 0.012 to 0.605 ± 0.072 hours. The mean elimination half-life ranged from 1.17 ± 0.26 to 2.02 ± 0.60 hours.12

Clearance

The total plasma clearance and renal clearance estimates of gadobenate ion were similar, ranging from 0.093 ± 0.010 to 0.133 ± 0.270 L/hr/kg and 0.082 ± 0.007 to 0.104 ± 0.039 L/hr/kg, respectively. The clearance is similar to that of substances that are subject to glomerular filtration.12

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, gadobenate dimeglumine has been shown to be teratogenic in rabbits following repeated intravenous administration during organogenesis at doses up to 6 times the recommended human dose. There were no adverse developmental effects observed in rats with intravenous administration of gadobenate dimeglumine during organogenesis at doses up to three times the recommended human dose. Because of the potential risks of gadolinium to the fetus, use gadobenate dimeglumine only if imaging is essential and cannot be delayed.12

Clinical consequences of overdosage with gadobenate dimeglumine have not been reported. Treatment of an overdosage should be directed toward support of vital functions and prompt institution of symptomatic therapy. In a Phase 1 clinical study, doses up to 0.4 mmol/kg were administered to patients. Gadobenate dimeglumine has been shown to be dialyzable.12

Long-term animal studies have not been performed to evaluate the carcinogenic potential of gadobenate dimeglumine.12

The results for gadobenate dimeglumine were negative in the following genetic toxicity studies: 1) in vitro bacteria reverse mutation assays, 2) an in vitro gene mutation assay in mammalian cells, 3) an in vitro chromosomal aberration assay, 4) an in vitro unscheduled DNA synthesis assay, and 5) an in vivo micronucleus assay in rats.12

Gadobenate dimeglumine had no effect on fertility and reproductive performance at IV doses of up to 2 mmol/kg/day (3 times the human dose on body surface basis) for 13 weeks in male rats and for 32 days in female rats. However, vacuolation in testes and abnormal spermatogenic cells were observed when gadobenate dimeglumine was intravenously administered to male rats at 3 mmol/kg/day (5 times the human dose on body surface basis) for 28 days. The effects were not reversible following 28-day recovery period. The effects were not reported in dog and monkey studies (at doses up to about 11 and 10 times the human dose on body surface basis for dogs (28 days dosing) and monkeys (14 days dosing), respectively).12

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.
Food Interactions
No interactions found.

Products

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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
MultiHanceInjection, solution529 mg/1mLIntravenousBracco Diagnostics Inc2004-11-23Not applicableUS flag
MultiHanceSolution529 mg / mLIntravenousBracco Imaging S.P.A.2004-10-28Not applicableCanada flag
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
MULTIHANCE INJECTION 10 MLGadobenate dimeglumine (529 mg/ml) + Gadobenate dimeglumine (529 mg/ml)InjectionIntravenousDCH AURIGA SINGAPORE2004-01-30Not applicableSingapore flag
MULTIHANCE INJECTION 10 MLGadobenate dimeglumine (529 mg/ml) + Gadobenate dimeglumine (529 mg/ml)InjectionIntravenousDCH AURIGA SINGAPORE2004-01-30Not applicableSingapore 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. 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]
  7. 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]
  8. Fakhran S, Alhilali L, Kale H, Kanal E: Assessment of rates of acute adverse reactions to gadobenate dimeglumine: review of more than 130,000 administrations in 7.5 years. AJR Am J Roentgenol. 2015 Apr;204(4):703-6. doi: 10.2214/AJR.14.13430. [Article]
  9. Ichikawa S, Omiya Y, Onishi H, Motosugi U: Linear gadolinium-based contrast agent (gadodiamide and gadopentetate dimeglumine)-induced high signal intensity on unenhanced T(1) -weighted images in pediatric patients. J Magn Reson Imaging. 2019 Apr;49(4):1046-1052. doi: 10.1002/jmri.26311. Epub 2018 Oct 11. [Article]
  10. 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]
  11. FDA Approved Drug Products: MultiHance (gadobenate dimeglumine) for injection [Link]
  12. FDA Approved Drug Products: MultiHance (gadobenate dimeglumine) Injection (Feb 2024) [Link]
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 Disorders1
4CompletedDiagnosticBrain Lesions1
4CompletedDiagnosticBrain Neoplasm1
4RecruitingDiagnosticColorectal Cancer / Hepatic Metastases / Oligometastatic Disease1

Pharmacoeconomics

Manufacturers
  • Bracco diagnostics inc
Packagers
  • Bracco Diagnostics Inc.
  • Nycomed Inc.
  • Patheon Inc.
Dosage Forms
FormRouteStrength
InjectionIntravenous0.529 g/ml
Injection, solutionIntravenous
Injection, solutionIntravenous529 mg/1mL
SolutionIntravenous334 mg/1ml
SolutionIntravenous529 mg / mL
Injection, solutionParenteral529 mg/ml
Injection, solutionParenteral0.5 mmol/ml
InjectionIntravenous529 mg/ml
InjectionIntravenous529 mg/ml
SolutionIntravenous10 ml
SolutionIntravenous15 ml
SolutionIntravenous20 ml
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
Liquid
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
Chromatographic Properties
Collision Cross Sections (CCS)
Not Available

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
No
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]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Organic anion transmembrane transporter activity
Specific Function
Mediates hepatobiliary excretion of numerous organic anions. May function as a cellular cisplatin transporter.
Gene Name
ABCC2
Uniprot ID
Q92887
Uniprot Name
Canalicular multispecific organic anion transporter 1
Molecular Weight
174205.64 Da
References
  1. FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
  2. FDA Approved Drug Products: MultiHance (gadobenate dimeglumine) Injection (Feb 2024) [Link]

Drug created at June 13, 2005 13:24 / Updated at June 19, 2024 12:15