Gadobutrol

Product Overview

Gadobutrol (development code ZK 135079) was developed by Bayer and marketed as Gadovist (EU and other regions) / Gadavist (US). It is a second-generation extracellular, non-ionic macrocyclic gadolinium-based contrast agent.

Structural characteristics: Gd³⁺ forms a neutral (non-ionic), macrocyclic, rigid chelate with the macrocyclic ligand butrol (dihydroxy-hydroxymethylpropyl-tetraazacyclododecane-triacetic acid, a DO3A derivative). The macrocyclic scaffold confers extremely high kinetic stability (slow decomplexation kinetics) and thermodynamic stability (log Keq ≈ 21.8; some sources report log K = 21–22).

Why 1.0 M is achievable: It is precisely this high stability that allows gadobutrol to be formulated at 1.0 mol/L — twice the concentration of most other GBCAs (0.5 mol/L). This delivers three direct clinical advantages:

1. Halved injection volume;
2. A more compact, higher-concentration bolus — improving dynamic enhancement and first-pass perfusion imaging;
3. At 1.0 M its viscosity is 4.96 mPa·s — higher than 0.5 M formulations, but still within an acceptable range.

The precise meaning of “high relaxivity”: In plasma at 1.5 T and 37 °C, r1 = 5.2 and r2 = 6.1 L·mmol⁻¹·s⁻¹. This is the highest among all macrocyclic GBCAs (for comparison: gadoteridol 4.1, gadoterate meglumine 3.6); however, compared with linear agents it is lower than gadobenate dimeglumine (6.3) and gadoxetate disodium (6.9). The accurate statement is therefore “the highest relaxivity among macrocyclic agents”, not “the highest among all gadolinium contrast agents”. Relaxivity shows minimal field-strength dependence.

In vivo behavior: Highly hydrophilic (n-butanol/pH 7.6 buffer partition coefficient approximately 0.006), virtually no plasma protein binding, and no inhibitory interaction with enzymes. After intravenous administration it rapidly distributes into the extracellular space, is not metabolized, and is excreted unchanged by glomerular filtration — renal clearance 1.1–1.7 mL/(min·kg), comparable to inulin; >50% is excreted in urine within 2 hours, >90% within 12 hours, and 100% within 72 hours of administration, with negligible extrarenal excretion; mean elimination half-life is approximately 1.8 hours, with dose-proportional kinetics. It does not cross the intact blood-brain barrier.

Technical Specifications

• Standards: CHP/USP/EP
• Specification: 0.99 (purity ≥99.0%); reagent/standard grades commonly ≥95% (calculated by gadolinium elemental analysis)
• CAS No.: 770691-21-9 (current CAS, adopted by CAS Common Chemistry, PubChem and Sigma; the former number 138071-82-6 has been replaced, although some Bayer product information still uses the old number); monohydrate 198637-52-4
• Molecular formula: C₁₈H₃₁GdN₄O₉; monohydrate C₁₈H₃₂GdN₄O₁₀
• Molecular weight: 604.71 (CAS, Sigma, TargetMol); various package inserts and PubChem report 604.72 (rounding difference); monohydrate 621.72; exact mass 605.1332
• Appearance: White to off-white / white to beige crystalline powder or solid; the monohydrate is a white to nearly white crystalline powder
• 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 macrocyclic metal chelate, 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 “per measured TGA/DSC” and do not recommend citing values from non-authoritative sources
• Specific optical rotation: Not found in pharmacopoeias or authoritative standards; the molecule contains (2R,3S) chiral centers (PubChem records 2 undefined stereocenters — a description difference for the racemic (1RS,2SR) form); quality control is typically achieved through gadolinium content, related substances, pH and osmolality
• Chemical name: 10-(2,3-Dihydroxy-1-hydroxymethylpropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid, gadolinium complex; also known as 2,2′,2″-[10-(1,3,4-trihydroxybutan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl]triacetic acid gadolinium(III)
• Solubility: Highly water-soluble, freely soluble in water (Sigma: H₂O 2 mg/mL, clear; the monohydrate is “completely soluble in water”); practically insoluble in organic solvents
• Thermodynamic stability constant: log Keq ≈ 21.8 (other sources report log K = 21–22)
• Relaxivity: 1.5 T, 37 °C, plasma: r1 = 5.2, r2 = 6.1 L·mmol⁻¹·s⁻¹; 0.47 T, 40 °C, pH 7: plasma r1 ≈ 5.6, r2 ≈ 6.5 (aqueous r1 ≈ 3.6, r2 ≈ 4.0). Relaxivity is only slightly dependent on field strength
• Formulation physicochemical parameters (1.0 mmol/mL injection, 37 °C): Contrast agent concentration 604.72 mg/mL (1.0 mmol/mL); osmolality 1603 mOsm/kg H₂O; osmolarity 1117 mOsm/L solution; viscosity 4.96 mPa·s; pH 6.6–8.0
• Computed physicochemical parameters: LogP approximately −6.7 (ligand-related calculated range); hydrogen bond donors 3 / acceptors 13; rotatable bonds 2; topological polar surface area approximately 194 Ų; heavy atom count 32; partition coefficient (n-butanol/pH 7.6 buffer) approximately 0.006
• Pharmacokinetic parameters: Negligible protein binding; not metabolized; renal clearance 1.1–1.7 mL/(min·kg); mean terminal half-life approximately 1.81 hours (range 1.33–2.13 hours)
• Storage conditions: Store sealed, protected from light and dry; powder recommended at 2–8 °C or −10 to −25 °C (supplier recommendations vary; Sigma recommends −10 to −25 °C); solutions should be aliquoted and stored at low temperature; injection should be stored tightly closed

Applications

• Contrast-enhanced magnetic resonance imaging (CE-MRI): For diagnostic use, intravenous administration only. Indicated for adults and pediatric patients of all ages (including term neonates) for CE-MRI of lesions in all body regions (including the brain and spinal cord). Superior diagnostic information compared with unenhanced imaging is obtained in regions where the blood-brain barrier is permeable or absent, perfusion is abnormal, or the extracellular space is enlarged (e.g., primary and secondary tumors, inflammatory diseases, demyelinating diseases). For brain and spinal cord imaging, optimal enhancement is generally observed within approximately 15 minutes of injection, and tissue enhancement generally persists up to 45 minutes after injection; T1-weighted sequences are particularly suitable for contrast-enhanced examinations
• Contrast-enhanced magnetic resonance angiography (CE-MRA): For CE-MRA of all body regions. Optimal imaging is observed during the arterial first pass after injection — the compact bolus afforded by the 1.0 M high concentration is particularly advantageous here
• Dosage and administration: Administered by intravenous rapid injection by physicians experienced in clinical MRI. The recommended adult dose is 0.1 mmol/kg body weight (equivalent to 0.1 mL/kg of the 1.0 M solution). If contrast-enhanced scanning shows no abnormality but clinical suspicion of a lesion remains high, or more precise information would influence treatment decisions, a further injection of up to 0.2 mmol/kg may be given within 30 minutes of the first dose to improve diagnostic accuracy. Dosing by field of view: single field of view — 7.5 mL for body weight <75 kg, 10 mL for ≥75 kg; more than one field of view — 15 mL for <75 kg, 20 mL for ≥75 kg. Pediatric patients (children and adolescents aged 2 years and above): 0.1 mmol/kg recommended. The lowest approved dose should be used whenever possible; patients should be observed for at least half an hour after administration (most adverse reactions occur within this window)
• Special populations: No dose adjustment is required in elderly patients (slightly higher AUC, slightly lower clearance); unless the diagnostic information is essential and cannot be obtained by other means, use should be avoided in patients with acute kidney injury or chronic severe kidney disease; congenital long QT syndrome should be excluded in pediatric patients before administration (in those who have not undergone ECG examination)
• Pharmacology and mechanism research: For T1/T2 relaxivity measurement and field-strength dependence studies; comparison of stability and gadolinium deposition between macrocyclic and linear gadolinium chelates; blood-brain barrier integrity assessment; extracellular space distribution and glomerular filtration studies; and as a model drug for high-concentration contrast agent bolus kinetics
• Formulation and manufacturing: For formulation development of the injection (1.0 mmol/mL; presentations 7.5 mL:4.5354 g, 15 mL:9.0708 g); excipients include calcobutrol sodium (approximately 0.513 mg/mL, chelating agent/stabilizer), tromethamine (approximately 1.211 mg/mL, buffer), hydrochloric acid and/or sodium hydroxide (pH adjustment), and water for injection; contains no antimicrobial preservative; each mL contains 0.00056 mmol sodium (approximately 0.013 mg). Key manufacturing control points include gadolinium content and complexation stability, free Gd³⁺, related substances, pH (6.6–8.0) and viscosity control at high concentration (4.96 mPa·s — the highest in its class and a parameter requiring focused validation in filling and injection processes); 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 physicians experienced in clinical MRI, in settings equipped with resuscitation equipment and personnel, and in compliance with standard MRI safety regulations (contraindicated with ferromagnetic implants, etc.). Boxed warning for gadolinium-based contrast agents (GBCA): Use of GBCAs in patients with impaired drug elimination increases the risk of nephrogenic systemic fibrosis (NSF); avoid use in high-risk patients unless the diagnostic information is essential and cannot be obtained with non-contrast MRI or other methods, do not exceed the recommended dose, and allow sufficient elimination time before repeat administration. Gadolinium retention: After use, gadolinium can be retained for months or years in the brain, bone, skin and other organs; the clinical consequences are unknown — although deposition is lower with macrocyclic agents than with linear agents, the lowest dose consistent with diagnosis should still be used. Contraindication: Previous severe allergic reaction to gadobutrol. Use with caution: history of contrast agent allergy, bronchial asthma, allergic disease, severe renal impairment, epilepsy, or cardiac arrhythmia. Common adverse reactions: feeling of skin warmth, injection-site reactions, nausea, altered taste, headache; serious adverse reactions include cardiac arrest, anaphylaxis, loss of consciousness, acute kidney injury and NSF. Overdose may affect cardiac repolarization and interfere with heart rhythm; ECG monitoring should be performed. When handling the API, wear protective gloves, protective clothing and eye/face protection, and avoid dust inhalation.

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