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
Weight
Average: 681.75
Monoisotopic: 682.11214
Chemical Formula
C23H30GdN3O11
Synonyms
  • Gadoxetate
  • Gadoxetic acid
  • Gd-EOB-DTPA

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

Reduce drug development failure rates
Build, train, & validate machine-learning models
with evidence-based and structured datasets.
See how
Build, train, & validate predictive machine-learning models with structured datasets.
See how
Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Diagnostic agentFocal liver disease•••••••••••••••••••••
Contraindications & Blackbox Warnings
Prevent Adverse Drug Events Today
Tap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.
Learn more
Avoid life-threatening adverse drug events with our Clinical API
Learn more
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 (Cltot) was 250 mL/min, whereas the renal clearance (Clr) 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
Improve decision support & research outcomes
With structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!
See the data
Improve decision support & research outcomes with our structured adverse effects data.
See a data sample
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.
DrugInteraction
AcetylcysteineThe excretion of Gadoxetic acid can be decreased when combined with Acetylcysteine.
Aminohippuric acidThe excretion of Gadoxetic acid can be decreased when combined with Aminohippuric acid.
AmprenavirThe excretion of Gadoxetic acid can be decreased when combined with Amprenavir.
ApalutamideThe serum concentration of Gadoxetic acid can be decreased when it is combined with Apalutamide.
AsunaprevirThe excretion of Gadoxetic acid can be decreased when combined with Asunaprevir.
Food Interactions
No interactions found.

Products

Drug product information from 10+ global regions
Our datasets provide approved product information including:
dosage, form, labeller, route of administration, and marketing period.
Access now
Access drug product information from over 10 global regions.
Access now
Product Ingredients
IngredientUNIICASInChI Key
Gadoxetate disodiumHOY74VZE0M135326-22-6SLYTULCOCGSBBJ-UHFFFAOYSA-I
Active Moieties
NameKindUNIICASInChI Key
Gadolinium cation (3+)ionicAZV954TZ9N22541-19-1RJOJUSXNYCILHH-UHFFFAOYSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
EovistInjection, solution181.43 mg/1mLIntravenousBayer HealthCare Pharmaceuticals Inc.2008-07-03Not applicableUS flag
PrimovistSolution181.43 mg / mLIntravenousBayer2010-02-04Not applicableCanada flag

Categories

ATC Codes
V08CA10 — Gadoxetic acid
Drug Categories
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]
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
PhaseStatusPurposeConditionsCount
4CompletedDiagnosticCirrhosis of the Liver1
4CompletedDiagnosticContrast Medium1
4CompletedDiagnosticHepatocellular Carcinoma1
4CompletedDiagnosticTransient Severe Arterial Phase Motion1
4RecruitingDiagnosticColorectal Cancer / Hepatic Metastases / Oligometastatic Disease1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solutionIntravenous181.43 mg/1mL
Injection
Injection, solution
SolutionIntravenous181.43 mg / mL
Injection, solutionIntravenous0.25 mmol
Injection, solutionParenteral0.25 mmol/ml
Injection, solutionIntravenous181.43 mg
Injection, solutionIntravenous bolus0.25 mmol/mL
SolutionIntravenous0.25 mmol
SolutionIntravenous181.43 mg/1ml
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US6039931No2000-03-212021-11-13US flag
US5798092No1998-08-252015-08-25US flag

Properties

State
Liquid
Experimental Properties
PropertyValueSource
pKa6.8-8MSDS
Predicted Properties
PropertyValueSource
Water Solubility0.497 mg/mLALOGPS
logP1.24ALOGPS
logP-4.3Chemaxon
logS-3.2ALOGPS
pKa (Strongest Acidic)1.98Chemaxon
pKa (Strongest Basic)9.99Chemaxon
Physiological Charge-3Chemaxon
Hydrogen Acceptor Count14Chemaxon
Hydrogen Donor Count2Chemaxon
Polar Surface Area213.94 Å2Chemaxon
Rotatable Bond Count20Chemaxon
Refractivity159.21 m3·mol-1Chemaxon
Polarizability50.67 Å3Chemaxon
Number of Rings1Chemaxon
Bioavailability0Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.6058
Blood Brain Barrier+0.6251
Caco-2 permeable-0.5137
P-glycoprotein substrateSubstrate0.6927
P-glycoprotein inhibitor INon-inhibitor0.6538
P-glycoprotein inhibitor IINon-inhibitor0.9495
Renal organic cation transporterNon-inhibitor0.6488
CYP450 2C9 substrateNon-substrate0.8375
CYP450 2D6 substrateNon-substrate0.8177
CYP450 3A4 substrateNon-substrate0.6054
CYP450 1A2 substrateNon-inhibitor0.6386
CYP450 2C9 inhibitorNon-inhibitor0.7982
CYP450 2D6 inhibitorNon-inhibitor0.6855
CYP450 2C19 inhibitorNon-inhibitor0.781
CYP450 3A4 inhibitorNon-inhibitor0.9528
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.7762
Ames testNon AMES toxic0.6871
CarcinogenicityNon-carcinogens0.8385
BiodegradationNot ready biodegradable0.6465
Rat acute toxicity2.2477 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.5
hERG inhibition (predictor II)Non-inhibitor0.7809
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

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. 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]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Organic anion transmembrane transporter activity
Specific Function
May act as an inducible transporter in the biliary and intestinal excretion of organic anions. Acts as an alternative route for the export of bile acids and glucuronides from cholestatic hepatocyte...
Gene Name
ABCC3
Uniprot ID
O15438
Uniprot Name
Canalicular multispecific organic anion transporter 2
Molecular Weight
169341.14 Da
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]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Atpase activity, coupled to transmembrane movement of substances
Specific Function
May be an organic anion pump relevant to cellular detoxification.
Gene Name
ABCC4
Uniprot ID
O15439
Uniprot Name
Multidrug resistance-associated protein 4
Molecular Weight
149525.33 Da
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]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostagland...
Gene Name
SLCO1B1
Uniprot ID
Q9Y6L6
Uniprot Name
Solute carrier organic anion transporter family member 1B1
Molecular Weight
76447.99 Da
References
  1. Nassif A, Jia J, Keiser M, Oswald S, Modess C, Nagel S, Weitschies W, Hosten N, Siegmund W, Kuhn JP: Visualization of hepatic uptake transporter function in healthy subjects by using gadoxetic acid-enhanced MR imaging. Radiology. 2012 Sep;264(3):741-50. doi: 10.1148/radiol.12112061. Epub 2012 Jul 6. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as 17-beta-glucuronosyl estradiol, taurocholate, triiodothyronine (T3), leukotriene C4, dehydroepiandrosterone sulfate (DHEAS), methotre...
Gene Name
SLCO1B3
Uniprot ID
Q9NPD5
Uniprot Name
Solute carrier organic anion transporter family member 1B3
Molecular Weight
77402.175 Da
References
  1. Nassif A, Jia J, Keiser M, Oswald S, Modess C, Nagel S, Weitschies W, Hosten N, Siegmund W, Kuhn JP: Visualization of hepatic uptake transporter function in healthy subjects by using gadoxetic acid-enhanced MR imaging. Radiology. 2012 Sep;264(3):741-50. doi: 10.1148/radiol.12112061. Epub 2012 Jul 6. [Article]

Drug created at May 22, 2013 21:49 / Updated at April 19, 2024 20:55