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

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MOLSDFPDBSMILESInChI

Similar Structures

Structure for Gadobenic acid (DB00743)

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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

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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 Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Diagnostic agent	Aortoiliac occlusive disease		••••••••••••	•••••• ••••••••• •••••••••		•••••••••• ••••••••
Diagnostic agent	Cns abnormal vascularity		••••••••••••	•••••• ••••••••• •••••••••		•••••••••• ••••••••
Diagnostic agent	Femoral artery occlusion		••••••••••••	•••••• ••••••••• •••••••••		•••••••••• ••••••••
Diagnostic agent	Femoral vein occlusion		••••••••••••	•••••• ••••••••• •••••••••		•••••••••• ••••••••
Diagnostic agent	Renal artery occlusion		••••••••••••	•••••• ••••••••• •••••••••		•••••••••• ••••••••

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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 C_max 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 AUC_0-∞ 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

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Interactions

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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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
Integrate drug-drug interactions in your software
Abacavir	Gadobenic acid may decrease the excretion rate of Abacavir which could result in a higher serum level.
Aceclofenac	Aceclofenac may decrease the excretion rate of Gadobenic acid which could result in a higher serum level.
Acemetacin	Acemetacin may decrease the excretion rate of Gadobenic acid which could result in a higher serum level.
Acetaminophen	Acetaminophen may decrease the excretion rate of Gadobenic acid which could result in a higher serum level.
Acetazolamide	Acetazolamide 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.

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Product Ingredients

Ingredient	UNII	CAS	InChI Key
Gadobenate dimeglumine	3Q6PPC19PO	127000-20-8	OCDAWJYGVOLXGZ-VPVMAENOSA-K

Active Moieties

Name	Kind	UNII	CAS	InChI Key
Gadolinium cation (3+)	ionic	AZV954TZ9N	22541-19-1	RJOJUSXNYCILHH-UHFFFAOYSA-N

International/Other Brands

Multihance Multipack (Bracco)

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
MultiHance	Injection, solution	529 mg/1mL	Intravenous	Bracco Diagnostics Inc	2004-11-23	Not applicable
MultiHance	Solution	529 mg / mL	Intravenous	Bracco Imaging S.P.A.	2004-10-28	Not applicable
MultiHance	Injection, solution	529 mg/1mL	Intravenous	Bracco Diagnostics Inc	2004-11-23	Not applicable

Mixture Products

Name	Ingredients	Dosage	Route	Labeller	Marketing Start	Marketing End	Region	Image
MULTIHANCE INJECTION 10 ML	Gadobenate dimeglumine (529 mg/ml) + Gadobenate dimeglumine (529 mg/ml)	Injection	Intravenous	DCH AURIGA SINGAPORE	2004-01-30	Not applicable
MULTIHANCE INJECTION 10 ML	Gadobenate dimeglumine (529 mg/ml) + Gadobenate dimeglumine (529 mg/ml)	Injection	Intravenous	DCH AURIGA SINGAPORE	2004-01-30	Not applicable

Categories

ATC Codes

V08CA08 — Gadobenic acid

• V08CA — Paramagnetic contrast media
• V08C — MAGNETIC RESONANCE IMAGING CONTRAST MEDIA
• V08 — CONTRAST MEDIA
• V — VARIOUS

Drug Categories

• Alcohols
• Amino Sugars
• Carbohydrates
• Compounds used in a research, industrial, or household setting
• Contrast Media
• Diagnostic Uses of Chemicals
• Drugs that are Mainly Renally Excreted
• Gadolinium-based Contrast Agent
• Hexosamines
• Magnetic Resonance Contrast Activity
• Magnetic Resonance Imaging Contrast Media
• Moderate Risk QTc-Prolonging Agents
• Other Diagnostics
• Paramagnetic Contrast Agent
• Paramagnetic Contrast Media
• QTc Prolonging Agents
• Sugar Alcohols

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]

External Links

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 Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">

Phase	Status	Purpose	Conditions	Count
4	Completed	Not Available	Brain Pathology	1
4	Completed	Diagnostic	Brain Disorders	1
4	Completed	Diagnostic	Brain Lesions	1
4	Completed	Diagnostic	Brain Neoplasm	1
4	Recruiting	Diagnostic	Colorectal Cancer / Hepatic Metastases / Oligometastatic Disease	1

Pharmacoeconomics

Manufacturers

• Bracco diagnostics inc

Packagers

• Bracco Diagnostics Inc.
• Nycomed Inc.
• Patheon Inc.

Dosage Forms

Form	Route	Strength
Injection	Intravenous	0.529 g/ml
Injection, solution	Intravenous
Injection, solution	Intravenous	529 mg/1mL
Solution	Intravenous	334 mg/1ml
Solution	Intravenous	529 mg / mL
Injection, solution	Parenteral	529 mg/ml
Injection, solution	Parenteral	0.5 mmol/ml
Injection	Intravenous	529 mg/ml
Injection	Intravenous	529 mg/ml
Solution	Intravenous	10 ml
Solution	Intravenous	15 ml
Solution	Intravenous	20 ml
Solution	Intravenous

Prices

Unit description	Cost	Unit
Multihance 529 mg/ml vial	6.87USD	ml

DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US4916246	No	1990-04-10	2012-04-10

Properties

State

Liquid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.768 mg/mL	ALOGPS
logP	0.92	ALOGPS
logP	-4.1	Chemaxon
logS	-3	ALOGPS
pKa (Strongest Acidic)	0.085	Chemaxon
pKa (Strongest Basic)	9.58	Chemaxon
Physiological Charge	-3	Chemaxon
Hydrogen Acceptor Count	14	Chemaxon
Hydrogen Donor Count	2	Chemaxon
Polar Surface Area	213.94 Å2	Chemaxon
Rotatable Bond Count	20	Chemaxon
Refractivity	154.36 m3·mol-1	Chemaxon
Polarizability	48.32 Å3	Chemaxon
Number of Rings	1	Chemaxon
Bioavailability	0	Chemaxon
Rule of Five	No	Chemaxon
Ghose Filter	No	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	No	Chemaxon

Predicted ADMET Features

Property	Value	Probability
Human Intestinal Absorption	-	0.9749
Blood Brain Barrier	-	0.9391
Caco-2 permeable	-	0.691
P-glycoprotein substrate	Substrate	0.8261
P-glycoprotein inhibitor I	Non-inhibitor	0.7702
P-glycoprotein inhibitor II	Non-inhibitor	0.7288
Renal organic cation transporter	Non-inhibitor	0.8635
CYP450 2C9 substrate	Non-substrate	0.8598
CYP450 2D6 substrate	Non-substrate	0.8006
CYP450 3A4 substrate	Non-substrate	0.6356
CYP450 1A2 substrate	Non-inhibitor	0.8637
CYP450 2C9 inhibitor	Non-inhibitor	0.8597
CYP450 2D6 inhibitor	Non-inhibitor	0.8675
CYP450 2C19 inhibitor	Non-inhibitor	0.8851
CYP450 3A4 inhibitor	Non-inhibitor	0.9349
CYP450 inhibitory promiscuity	Low CYP Inhibitory Promiscuity	0.9905
Ames test	Non AMES toxic	0.8062
Carcinogenicity	Non-carcinogens	0.9179
Biodegradation	Not ready biodegradable	0.8088
Rat acute toxicity	2.3557 LD50, mol/kg	Not applicable
hERG inhibition (predictor I)	Weak inhibitor	0.8499
hERG inhibition (predictor II)	Non-inhibitor	0.6371

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

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Drug created at June 13, 2005 13:24 / Updated at February 20, 2024 23:55