Gadoxetic acid

Identification

Summary

Gadoxetic acid is a gadolinium-based contrast agent (GBCA) used with contrasted magnetic resonance imaging (MRI) to detect and visualize the liver.

Brand Names

Eovist, Primovist

Generic Name

Gadoxetic acid

DrugBank Accession Number

DB08884

Background

Gadoxetic acid (gadoxetate) is a paramagnetic gadolinium-containing ionic linear contrast agent in which its salt form, gadoxetate disodium, is used for intravenous injection. Ethoxybenzyl diethylenetriaminepentaacetic acid is the moiety that chelates with a gadolinium ion and forms a stable complex with it to make up the drug.⁴ Gadoxetate is a unique gadolinium-based contrasting agent (GBCA) with both dynamic phase and hepatobiliary phase and thus has different pharmacokinetic and pharmacodynamic properties compared to other GBCAs.² Since gadoxetate uptake is mediated by organic anion-transporting polypeptides (OATPs) and liver tumor cells lack OATPs, liver tumors show a lack of contrast of enhancement and therefore heightening the liver parenchyma-liver tumours contrast.²

Gadoxetic acid, under the form gadoxetate disodium, is marketed by Bayer HealthCare Pharmaceuticals under the brand name EOVIST and FDA approved in 2008.³

Type

Small Molecule

Groups

Approved

Structure

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MOLSDFPDBSMILESInChI

Similar Structures

Structure for Gadoxetic acid (DB08884)

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Weight

Average: 681.75
Monoisotopic: 682.11214

Chemical Formula

C₂₃H₃₀GdN₃O₁₁

Synonyms

• Gadoxetate
• Gadoxetic acid
• Gd-EOB-DTPA

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Pharmacology

Indication

Gadoxetate is indicated for intravenous use in magnetic resonance imaging (MRI) of the liver to detect and characterize lesions in patients with known or suspected focal liver disease.⁵

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Diagnostic agent	Focal liver disease		••••••••••••			•••••••••

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Pharmacodynamics

EOB-DTPA forms a stable complex with the paramagnetic gadolinium ion with a thermodynamic stability of log KGdL=-23.46. Gadoxetate disodium is a highly water-soluble, hydrophilic compound with a lipophilic moiety, the ethoxybenzyl group (EOB).⁵

Gadoxetate disodium is selectively taken up by hepatocytes resulting in increased signal intensity in liver tissue.⁵

Gadoxetate disodium exhibits a biphasic mode of action: first, distribution in the extracellular space after injection and subsequently, selective uptake by hepatocytes (and biliary excretion) due to the lipophilic (EOB) moiety.⁵

Mechanism of action

Gadoxetate disodium is a paramagnetic compound and develops a magnetic moment when placed in a magnetic field. The relatively large magnetic moment produced by gadoxetate disodium results in a local magnetic field, yielding enhanced relaxation rates (shortening of relaxation times) of water protons in the vicinity of the paramagnetic agent, which leads to an increase in signal intensity (brightening) of blood and tissue.⁵

In 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, gadoxetate disodium decreases the T₁ and T₂ relaxation time in target tissue. At the recommended dose, the effect is observed with the greatest sensitivity in T₁-weighted MR sequences.⁵

Absorption

After intravenous administration, the plasma concentration-time profile of gadoxetate disodium is characterized by a biexponential decline.⁵

Volume of distribution

The total volume of distribution at steady state of gadoxetate disodium is 0.21 L/kg.⁵

Protein binding

Gadoxetate disodium shows a weak (<10%), transient protein binding and the relaxivity in plasma is about 8.7 L/mmol/sec at pH 7, 39°C and 0.47 T.⁵ Because it is more protein-bound than other gadolinium-based contrast agents, gadoxetate disodium has increased T1 relaxivity and thus enhanced signal generation.²

Metabolism

Gadoxetate disodium is not metabolized.⁵

Route of elimination

Gadoxetate disodium is equally eliminated via the renal and hepatobiliary routes.⁵ Biliary excretion is attributed to the Multidrug Resistance Protein 2.¹

Half-life

The mean terminal elimination half-life of gadoxetate disodium (0.01 to 0.1 mmol/kg) has been observed in healthy volunteers of 22–39 years of age to be 0.91 to 0.95 hours.⁵

Clearance

A total serum clearance (Cl_tot) was 250 mL/min, whereas the renal clearance (Cl_r) corresponds to about 120 mL/min, a value similar to the glomerular filtration rate in healthy subjects. Clearance appeared to decrease slightly with increasing age.⁵

Adverse Effects

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Toxicity

GBCAs have been shown to 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, no teratogenicity was observed with repeated daily intravenous administration of gadoxetate disodium to rats during organogenesis at doses up to 32 times the recommended single human dose; however, an increase in preimplantation loss was noted at doses 3.2 times the single human dose. Post-implantation loss was observed with repeated daily intravenous administration of gadoxetate disodium to rabbits on gestation days 6 through 18 at doses 26 times the recommended single human dose (see Data). Because of the potential risks of gadolinium to the fetus, use gadoxetate disodium only if imaging is essential during pregnancy and cannot be delayed.⁵

The maximum dose studied in MR imaging was 0.4 mL/kg (0.1 mmol/kg) body weight and was tolerated in a manner similar to lower doses. In case of inadvertent overdosage in patients with severely impaired renal and/or hepatic function, gadoxetate disodium can be partially removed by hemodialysis.⁵

No carcinogenicity studies of gadoxetate disodium have been conducted.⁵

Gadoxetate disodium was not mutagenic in in vitro reverse mutation tests in bacteria, or in chromosome aberration tests in human peripheral blood lymphocytes, and was negative in an in vivo micronucleus test in mice after intravenous injection of doses up to 4 mmol/kg.⁵

Gadoxetate disodium had no effect on fertility and general reproductive performance of male and female rats when given in doses 6.5 times the human dose (based on body surface area).⁵

A dose-related increase in QTc which was resolved by 30 minutes post dosing was observed in dogs when given a single dose of gadoxetate disodium. The increase was noted when given in doses equal to or greater than 0.1 mmol/kg (2.2 times the human dose). Maximum increase in QTcF was equal to or less than 20 ms at doses up to 0.5 mmol/kg (11 times the human dose).⁵

A gait disturbance was observed in 1 of 3 mice when given gadoxetate disodium at a dose of approximately 1.1 mmol/kg (3.6 times the human dose); the disturbance occurred at 30 minutes post dosing and resolved at 4 hours post dosing.⁵

Local intolerance reactions, including moderate interstitial hemorrhage, edema, and focal muscle fiber necrosis, were observed after intramuscular administration of gadoxetate disodium.⁵

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.

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

Drug	Interaction
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Acetylcysteine	The excretion of Gadoxetic acid can be decreased when combined with Acetylcysteine.
Aminohippuric acid	The excretion of Gadoxetic acid can be decreased when combined with Aminohippuric acid.
Amprenavir	The excretion of Gadoxetic acid can be decreased when combined with Amprenavir.
Apalutamide	The serum concentration of Gadoxetic acid can be decreased when it is combined with Apalutamide.
Asunaprevir	The excretion of Gadoxetic acid can be decreased when combined with Asunaprevir.

Food Interactions

No interactions found.

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Product Ingredients

Ingredient	UNII	CAS	InChI Key
Gadoxetate disodium	HOY74VZE0M	135326-22-6	SLYTULCOCGSBBJ-UHFFFAOYSA-I

Active Moieties

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

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Eovist	Injection, solution	181.43 mg/1mL	Intravenous	Bayer HealthCare Pharmaceuticals Inc.	2008-07-03	Not applicable
Primovist	Solution	181.43 mg / mL	Intravenous	Bayer	2010-02-04	Not applicable

Categories

ATC Codes

V08CA10 — Gadoxetic acid

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

Drug Categories

• Acetates
• Acids, Acyclic
• Amines
• Compounds used in a research, industrial, or household setting
• Contrast Media
• Coordination Complexes
• Diagnostic Uses of Chemicals
• Gadolinium-based Contrast Agent
• Magnetic Resonance Contrast Activity
• Magnetic Resonance Imaging Contrast Media
• OATP1B1/SLCO1B1 Substrates
• OATP1B3 substrates
• Other Diagnostics
• Paramagnetic Contrast Agent
• Paramagnetic Contrast Media
• Polyamines

Classification

Not classified

Affected organisms

• Humans and other mammals

Chemical Identifiers

UNII

3QJA87N40S

CAS number

135326-11-3

InChI Key

PCZHWPSNPWAQNF-LMOVPXPDSA-K

InChI

InChI=1S/C23H33N3O11.Gd/c1-2-37-18-5-3-16(4-6-18)9-17(26(14-22(33)34)15-23(35)36)10-24(11-19(27)28)7-8-25(12-20(29)30)13-21(31)32;/h3-6,17H,2,7-15H2,1H3,(H,27,28)(H,29,30)(H,31,32)(H,33,34)(H,35,36);/q;+3/p-3/t17-;/m0./s1

IUPAC Name

gadolinium(3+) ion 2-[(2-{[(2S)-2-[bis(carboxymethyl)amino]-3-(4-ethoxyphenyl)propyl](carboxylatomethyl)amino}ethyl)(carboxylatomethyl)amino]acetate

SMILES

[Gd+3].[H][C@@](CN(CCN(CC([O-])=O)CC([O-])=O)CC([O-])=O)(CC1=CC=C(OCC)C=C1)N(CC(O)=O)CC(O)=O

References

General References

1. Van Beers BE, Pastor CM, Hussain HK: Primovist, Eovist: what to expect? J Hepatol. 2012 Aug;57(2):421-9. doi: 10.1016/j.jhep.2012.01.031. Epub 2012 Apr 12. [Article]
2. Choi Y, Huh J, Woo DC, Kim KW: Use of gadoxetate disodium for functional MRI based on its unique molecular mechanism. Br J Radiol. 2016;89(1058):20150666. doi: 10.1259/bjr.20150666. Epub 2015 Dec 23. [Article]
3. Ringe KI, Boll DT, Husarik DB, Bashir MR, Gupta RT, Merkle EM: Lesion detection and assessment of extrahepatic findings in abdominal MRI using hepatocyte specific contrast agents--comparison of Gd-EOB-DTPA and Gd-BOPTA. BMC Med Imaging. 2013 Mar 18;13:10. doi: 10.1186/1471-2342-13-10. [Article]
4. Ye F, Liu J, Ouyang H: Gadolinium Ethoxybenzyl Diethylenetriamine Pentaacetic Acid (Gd-EOB-DTPA)-Enhanced Magnetic Resonance Imaging and Multidetector-Row Computed Tomography for the Diagnosis of Hepatocellular Carcinoma: A Systematic Review and Meta-analysis. Medicine (Baltimore). 2015 Aug;94(32):e1157. doi: 10.1097/MD.0000000000001157. [Article]
5. FDA Approved Drug Products: EOVIST (gadoxetate disodium) injection, for intravenous use [Link]

External Links

KEGG Drug

D04288

PubChem Compound

131704314

PubChem Substance

175427133

ChemSpider

189907

RxNav

802624

ChEMBL

CHEMBL1201768

PharmGKB

PA165985534

RxList

RxList Drug Page

Drugs.com

Drugs.com Drug Page

Wikipedia

Gadoxetic_acid

FDA label

Download (223 KB)

MSDS

Download (114 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Completed	Diagnostic	Cirrhosis of the Liver	1
4	Completed	Diagnostic	Contrast Medium	1
4	Completed	Diagnostic	Hepatocellular Carcinoma	1
4	Completed	Diagnostic	Transient Severe Arterial Phase Motion	1
4	Recruiting	Diagnostic	Colorectal Cancer / Hepatic Metastases / Oligometastatic Disease	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Injection, solution	Intravenous	181.43 mg/1mL
Injection
Injection, solution
Solution	Intravenous	181.43 mg / mL
Injection, solution	Intravenous	0.25 mmol
Injection, solution	Parenteral	0.25 mmol/ml
Injection, solution	Intravenous	181.43 mg
Injection, solution	Intravenous bolus	0.25 mmol/mL
Solution	Intravenous	0.25 mmol
Solution	Intravenous	181.43 mg/1ml

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US6039931	No	2000-03-21	2021-11-13
US5798092	No	1998-08-25	2015-08-25

Properties

State

Liquid

Experimental Properties

Property	Value	Source
pKa	6.8-8	MSDS

Predicted Properties

Property	Value	Source
Water Solubility	0.497 mg/mL	ALOGPS
logP	1.24	ALOGPS
logP	-4.3	Chemaxon
logS	-3.2	ALOGPS
pKa (Strongest Acidic)	1.98	Chemaxon
pKa (Strongest Basic)	9.99	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	159.21 m3·mol-1	Chemaxon
Polarizability	50.67 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	+	0.6058
Blood Brain Barrier	+	0.6251
Caco-2 permeable	-	0.5137
P-glycoprotein substrate	Substrate	0.6927
P-glycoprotein inhibitor I	Non-inhibitor	0.6538
P-glycoprotein inhibitor II	Non-inhibitor	0.9495
Renal organic cation transporter	Non-inhibitor	0.6488
CYP450 2C9 substrate	Non-substrate	0.8375
CYP450 2D6 substrate	Non-substrate	0.8177
CYP450 3A4 substrate	Non-substrate	0.6054
CYP450 1A2 substrate	Non-inhibitor	0.6386
CYP450 2C9 inhibitor	Non-inhibitor	0.7982
CYP450 2D6 inhibitor	Non-inhibitor	0.6855
CYP450 2C19 inhibitor	Non-inhibitor	0.781
CYP450 3A4 inhibitor	Non-inhibitor	0.9528
CYP450 inhibitory promiscuity	Low CYP Inhibitory Promiscuity	0.7762
Ames test	Non AMES toxic	0.6871
Carcinogenicity	Non-carcinogens	0.8385
Biodegradation	Not ready biodegradable	0.6465
Rat acute toxicity	2.2477 LD50, mol/kg	Not applicable
hERG inhibition (predictor I)	Weak inhibitor	0.5
hERG inhibition (predictor II)	Non-inhibitor	0.7809

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 May 22, 2013 21:49 / Updated at April 14, 2024 23:44