Gadoxetate Disodium

Product Overview

Gadoxetate disodium (Gd-EOB-DTPA, development code ZK 139834) was developed by Bayer and marketed as Primovist (EU and other regions) / Eovist (US). It was approved by the FDA on July 3, 2008, and approved in New Zealand and other regions in March 2012. A gadoxetate disodium injection is also marketed in China.

The ingenuity of its structural design: It is an amphipathic derivative obtained by covalently introducing a lipophilic ethoxybenzyl (EOB) group onto the backbone of the classic gadolinium contrast agent Gd-DTPA (gadopentetate dimeglumine). This modification brings three key changes:

1. Hepatocyte targeting — the EOB group enables the molecule to be taken up by normally functioning hepatocytes via organic anion transporting polypeptides (OATP, mainly OATP1B1/1B3), and then excreted into bile via multidrug resistance-associated proteins (MRP2, etc.). Normal liver tissue is thereby enhanced, whereas lesion tissues such as hepatocellular carcinoma and metastases, which lack functional hepatocytes, take up virtually none — creating a sharp contrast.
2. Increased protein binding — plasma protein binding is higher than that of other gadolinium contrast agents (literature reports <10%, but higher than other GBCAs), yielding a higher T1 relaxivity: approximately 6.9 L·mmol⁻¹·s⁻¹ in plasma at 1.5 T, with more pronounced signal enhancement.
3. Dual-pathway excretion — approximately 50% excreted renally and 50% hepatically/biliary, enabling both hepatobiliary-phase imaging and assessment of biliary drainage.

Imaging principle: Gd³⁺ is a lanthanide metal ion with 7 unpaired electrons; when placed in a magnetic field it generates a large magnetic moment and local magnetic field, shortening the T1 and T2 relaxation times of surrounding water protons. At the recommended dose, observation with T1-weighted sequences is most sensitive, manifesting as increased tissue signal (brightening).

Chelation stability: EOB-DTPA forms a complex with Gd³⁺ of extremely high thermodynamic stability, with a thermodynamic stability constant of log K_GdL = 23.46 (some literature records −23.46, a difference in sign convention), which helps reduce the risk of free gadolinium ion release.

Technical Specifications

• Standards: CHP/USP/EP
• Specification: 0.99 (purity ≥99.0%); reagent/standard grades commonly ≥95% (calculated by gadolinium elemental analysis, Sigma-Aldrich) or ≥98%
• CAS No.: 135326-22-6 (EINECS 218-362-5; UNII; KEGG DRUG D04288; DrugBank DB08884; ATC V08CA10; PubChem CID 450096/9961939)
• Molecular formula: C₂₃H₂₈GdN₃Na₂O₁₁ (may also be written as C₂₃H₂₈N₃O₁₁Gd·2Na or GdC₂₃H₂₈N₃O₁₁Na₂)
• Molecular weight: 725.71 (consistent across Sigma-Aldrich, Alfa Chemistry, ChemicalBook and MCE); the FDA label and Chinese package inserts report 725.72 (rounding difference). Exact mass depends on isotopic composition
• Appearance: White to off-white / white to beige crystalline powder or solid; strongly hygroscopic, must be stored with desiccant
• Purity (HPLC / gadolinium elemental analysis): ≥ 99.0%
• Melting point: No official melting point has been found in CHP/USP/EP or in published FDA/EMA documentation. As a metal chelate salt, it typically decomposes at elevated temperature rather than melting; industry practice is to substitute melting-point testing with thermogravimetric analysis (TGA) / differential scanning calorimetry (DSC) together with controls for moisture, gadolinium content and related substances; if this field is mandatory on the site, we recommend entering “not applicable” or “≥250 °C decomposes (per measurement)” and do not recommend citing values from non-authoritative sources
• Specific optical rotation: Not found in pharmacopoeias or authoritative standards; the molecule contains a (4S) chiral center; quality control is typically achieved through chiral HPLC/enantiomeric purity and structural confirmation (NMR, MS, gadolinium content)
• Chemical name: (4S)-4-(4-Ethoxybenzyl)-3,6,9-tris(carboxymethyl)-3,6,9-triazaundecanedioic acid, gadolinium complex, disodium salt; IUPAC: disodium 2-[[2-[bis(carboxylatomethyl)amino]-3-(4-ethoxyphenyl)propyl]-[2-[bis(carboxylatomethyl)amino]ethyl]amino]acetate gadolinium(3+)
• Stereochemistry: (4S) single configuration
• Solubility: Highly water-soluble (Sigma-Aldrich: H₂O 2 mg/mL, clear; described in literature as highly water soluble); soluble in DMSO; practically insoluble in organic solvents. n-Butanol/pH 7.6 buffer partition coefficient approximately 0.011 (extremely hydrophilic)
• Formulation physicochemical parameters (0.25 mmol/mL injection, 37 °C): Osmolality 688 mOsm/kg H₂O; viscosity 1.19 mPa·s; density 1.088 g/mL; pH 6.8–8.0
• Stability constant: log K_GdL = 23.46
• T1 relaxivity: Approximately 6.9 L·mmol⁻¹·s⁻¹ (1.5 T, plasma); relaxivity decreases slightly with increasing field strength
• Pharmacokinetic parameters: Plasma protein binding <10%; terminal half-life in healthy adults approximately 0.91–0.95 hours; total serum clearance approximately 250 mL/min, renal clearance approximately 120 mL/min; not metabolized; approximately 50% excreted in urine and 50% in feces (bile); transporters involved include OATP1B1/1B3 (uptake) and MRP2/ABCC2, ABCC3, ABCC4 (efflux)
• Computed physicochemical parameters: LogP approximately −7.35; hydrogen bond acceptors 14, donors 0; topological polar surface area approximately 219.6 Ų
• Storage conditions: Strongly hygroscopic — store sealed, with desiccant, protected from light; Sigma-Aldrich recommends −10 to −25 °C; other sources recommend 2–8 °C under inert gas (nitrogen or argon), or 4 °C sealed and moisture-proof; solutions should be aliquoted — stable 6 months at −80 °C and 1 month at −20 °C

Applications

• Detection and characterization of focal liver lesions (core indication): For diagnostic use, intravenous administration only. Provides characterization information for focal liver lesions (e.g., hepatocellular carcinoma, liver metastases, benign lesions) in T1-weighted magnetic resonance imaging, for lesion detection and characterization. Three pivotal phase III studies showed that the combination of unenhanced MRI and gadoxetate-enhanced MRI achieved a statistically significant improvement in lesion detection sensitivity compared with unenhanced MRI alone
• Dosage and administration: Adults: 0.1 mL/kg body weight (equivalent to 0.025 mmol/kg); administer by bolus intravenous injection through a large-bore needle or indwelling catheter (18–20 G recommended) at a rate of 1–2 mL/s, followed by a flush of 5 mL of 0.9% sodium chloride injection to ensure complete delivery of the drug. No dose adjustment is required in elderly (≥65 years), hepatically impaired or renally impaired patients, but caution is required in patients with severe renal impairment
• Hepatobiliary phase imaging (HBP): Because approximately 50% is taken up by hepatocytes and excreted into bile, hepatocyte-specific enhancement can be obtained in the delayed (hepatobiliary) phase after injection, for assessing liver function, biliary anatomy and drainage, and for differentiating benign lesions containing functional hepatocytes (e.g., focal nodular hyperplasia) from malignant lesions lacking hepatocytes
• Biliary system imaging: Its biliary excretion property enables MRI visualization of the gallbladder and bile ducts
• Pharmacology and mechanism research: For OATP/MRP transporter studies, hepatocyte uptake and biliary excretion mechanisms, T1/T2 relaxivity measurement, and evaluation of gadolinium chelate stability and free gadolinium release
• Formulation and manufacturing: For formulation development of the injection (181.43 mg/mL, equivalent to 0.25 mmol/mL; 10 mL prefilled glass syringe); excipients include caloxetate trisodium (chelating agent), tromethamine (buffer), hydrochloric acid/sodium hydroxide (pH adjustment), and no antimicrobial preservative. Key manufacturing control points include gadolinium content and complexation stability, free Gd³⁺, related substances, pH (6.8–8.0) and osmolality, as well as moisture control arising from the API’s hygroscopicity; suitable for analytical method development and validation, stability studies, and GMP scale-up and CMO/CDMO contract manufacturing

Safety notice: This product is an active pharmaceutical ingredient (API) intended solely for legitimate industrial, research and pharmaceutical manufacturing use, and does not constitute end-user clinical or self-administration guidance. The finished product is a prescription drug and must be used by specialist radiologists in settings equipped with resuscitation equipment and personnel. Warnings for gadolinium-based contrast agents (GBCA): Use of GBCAs in patients with severe renal impairment may increase the risk of nephrogenic systemic fibrosis (NSF); renal function should be assessed before administration. In patients with end-stage renal failure, the terminal half-life is prolonged approximately 12-fold, AUC is increased approximately 6-fold, and hepatic enhancement is markedly reduced. Hypersensitivity reactions (including anaphylaxis) have been reported. The most common adverse reactions (≥0.5%) are nausea, headache, feeling of warmth, dizziness and back pain. In overdose, the drug can be partially removed by hemodialysis (a single 3-hour dialysis session removes approximately 30% of the administered dose). The API is GHS-classified as acute oral toxicity category 4, skin irritation category 2, eye irritation category 2, and specific target organ toxicity (respiratory irritation) category 3 (H302/H315/H319/H335); when handling, wear protective gloves, protective clothing and eye/face protection, and avoid dust inhalation.

Product information: please contact us. This information is for reference only.