Gadobenic acid

Identification

Name
Gadobenic acid
Accession Number
DB00743  (APRD00989)
Type
Small Molecule
Groups
Approved
Description

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.

Structure
Thumb
Synonyms
  • Acide gadobenique
  • Acido gadobenico
  • Acidum gadobenicum
  • Gadobenate
  • Gadobenic acid
  • Gadobensäure
External IDs
B 19036 / B 19036/7
Product Ingredients
IngredientUNIICASInChI Key
Gadobenate dimeglumine3Q6PPC19PO127000-20-8OCDAWJYGVOLXGZ-VPVMAENOSA-K
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
MultiHanceSolution529 mgIntravenousBracco Imaging S.P.A.2004-10-28Not applicableCanada
MultiHanceInjection, solution529 mg/mLIntravenousBracco Diagnostics, Inc2004-11-23Not applicableUs
MultiHanceInjection, solution529 mg/mLIntravenousBracco Diagnostics, Inc2004-11-23Not applicableUs
International/Other Brands
Multihance Multipack (Bracco)
Categories
UNII
15G12L5X8K
CAS number
113662-23-0
Weight
Average: 667.73
Monoisotopic: 668.09649
Chemical Formula
C22H28GdN3O11
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

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.

Structured Indications
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]
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.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

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. [PubMed:10608412]
  2. Morana G, Salviato E, Guarise A: Contrast agents for hepatic MRI. Cancer Imaging. 2007 Oct 1;7 Spec No A:S24-7. [PubMed:17921081]
  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. [PubMed:1546612]
  4. Kirchin MA, Pirovano GP, Spinazzi A: Gadobenate dimeglumine (Gd-BOPTA). An overview. Invest Radiol. 1998 Nov;33(11):798-809. [PubMed:9818314]
  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. [PubMed:10608397]
  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]
External Links
KEGG Drug
D08018
PubChem Compound
131704172
PubChem Substance
46506805
ChemSpider
94843
ChEMBL
CHEMBL1200571
Therapeutic Targets Database
DAP001225
PharmGKB
PA164745426
Wikipedia
Gadobenic_acid
ATC Codes
V08CA08 — Gadobenic acid
AHFS Codes
  • 36:89.00* — Other Diagnostics
FDA label
Download (247 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedDiagnosticCentral Nervous System Pathology1
2CompletedDiagnosticCoronary Artery Disease / Nonvalvular Atrial Fibrillation1
2RecruitingDiagnosticBlood Brain Barrier Defect / CNS Lesion1
2TerminatedDiagnosticChronic Thromboembolic Pulmonary Hypertension / Pulmonary Arterial Hypertension (PAH)1
3CompletedDiagnosticCancer, Breast1
3CompletedDiagnosticCarotid, Aortic, Renal or Peripheral Artery Disease1
3CompletedDiagnosticPeripheral Vascular Disease (PVD)1
3CompletedDiagnosticSteno-Occlusive Disease1
3TerminatedDiagnosticCentral Nervous System Diseases1
4CompletedNot AvailableBrain Pathology1
4CompletedDiagnosticBrain Lesions1
4CompletedDiagnosticNeoplasms, Brain1
Not AvailableCompletedNot AvailableCentral Nervous System Disease / Central Nervous System Neoplasms1
Not AvailableCompletedNot AvailableLiver Lesion / Neoplasms, Hepatic1
Not AvailableCompletedDiagnosticHepatocellular,Carcinoma1
Not AvailableNot Yet RecruitingDiagnosticIntracranial Neoplasm1
Not AvailableRecruitingNot AvailableCentral Nervous System Diseases / Central Nervous System Neoplasms1
Not AvailableRecruitingNot AvailableCoronary Artery Disease / Coronary Microvascular Disease1
Not AvailableRecruitingNot AvailableDotarem / Gadolinium / Gadolinium Retention / Magnetic Resonance Imaging (MRI) / MultiHance1
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
Not AvailableWithdrawnScreeningCardiac Graft1

Pharmacoeconomics

Manufacturers
  • Bracco diagnostics inc
Packagers
Dosage forms
FormRouteStrength
Injection, solutionIntravenous529 mg/mL
SolutionIntravenous529 mg
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)
US4916246No1995-04-102012-04-10Us

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

Taxonomy

Classification
Not classified

Carriers

Kind
Protein
Organism
Human
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. [PubMed:16118549]
  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. [PubMed:9055236]
  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. [PubMed:9406019]
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]

Drug created on June 13, 2005 07:24 / Updated on January 22, 2018 10:46