Chemical formula: C₂₃H₃₀GdN₃O₁₁ Molecular mass: 681.75 g/mol PubChem compound: 131704314
Gadoxetic acid is a paramagnetic contrast agent for magnetic resonance imaging.
The contrast-enhancing effect is mediated by gadoxetate (Gd EOB DTPA), an ionic complex consisting of gadolinium (III) and the ligand ethoxybenzyl-diethylenetriamine-pentaacetic acid (EOB-DTPA).
When T1-weighted scanning sequences are used in proton magnetic resonance imaging, the gadolinium ion-induced shortening of the spin-lattice relaxation time of excited atomic nuclei leads to an increase of the signal intensity and, hence, to an increase of the image contrast of certain tissues.
Gadoxetate disodium leads to a distinct shortening of the relaxation times even at low concentrations. At pH 7, a magnetic field strength of 0.47 T and 40°C the relaxivity (r1) - determined from the influence on the spin-lattice relaxation time (T1) of protons in plasma – is about 8.18 l/mmol/sec and the relaxivity (r2) - determined from the influence on the spin-spin relaxation time (T2) - is about 8.56 l/mmol/sec. At 1.5 T and 37°C the respective relaxivities in plasma are r1 = 6.9 l/mmol/sec and r2 = 8.7 l/mmol/sec. The relaxivity displays a slight inverse dependency on the strength of the magnetic field.
EOB-DTPA forms a stable complex with the paramagnetic gadolinium ion with extremely high thermodynamic stability (log KGdl = 23.46). Gd-EOB-DTPA is a highly water-soluble, hydrophilic compound with a partition coefficient between n-butanol and buffer at pH 7.6 of about 0.011. Due to its lipophilic ethoxybenzyl moiety gadoxetate disodium exhibits a biphasic mode of action: first, distribution in the extracellular space after bolus injection and subsequently selective uptake by hepatocytes. The relaxivity r1 in liver tissue is 16.6 l/mmol/sec (at 0.47T) resulting in increased signal intensity of liver tissue. Subsequently gadoxetate disodium is excreted into the bile.
Lesions with no or minimal hepatocyte function (cysts, metastases, the majority of hepatocellular carcinoma) will not accumulate gadoxetic acid. Well-differentiated hepatocellular carcinoma may contain functioning hepatocytes and can show some enhancement in the hepatocyte imaging phase. Additional clinical information is therefore needed to support a correct diagnosis.
The substance does not display any significant inhibitory interaction with enzymes at clinically relevant concentrations.
After bolus injection of gadoxetic acid, dynamic imaging during arterial, portovenous and equilibrium phases utilizes the different temporal enhancement pattern of different liver lesions as basis for the radiological lesion characterization.
The enhancement of liver parenchyma during the hepatocyte phase assists in the identification of the number, segmental distribution, visualization, and delineation of liver lesions, thus improving lesion detection. The differential enhancement/washout pattern of liver lesions contributes to the information from the dynamic phase.
The delayed (hepatocyte) phase can be investigated at 20 minutes post injection with an imaging window lasting at least 120 minutes. The diagnostic and technical efficacy results of the clinical studies show a minimal improvement at 20 minutes post injection over those at 10 minutes post injection.
The imaging window is reduced to 60 minutes in patients requiring hemodialysis and in patients with elevated bilirubin values (>3 mg/dl).
Hepatic excretion of gadoxetic acid results in enhancement of biliary structures.
The physico-chemical characteristics of the ready-to-use solution of gadoxetic acid are as follows:
| Osmolality at 37°C (mOsm/kg H2O) | 688 |
| Viscosity at 37°C (mPa·s) | 1.19 |
| Density at 37°C (g/ ml) | 1.0881 |
| pH | 7.4 |
After intravenous administration the concentration time profile of Gd-EOB-DTPA was characterised by a bi-exponential decline.
Gd-EOB-DTPA distributes in the extracellular space (distribution volume at steady state about 0.21 l/kg).
The substance elicits only minor protein binding (less than 10%).
The compound diffuses through the placental barrier only to a small extent.
Gadoxetate disodium is a linear GdCA. Studies have shown that after exposure to GdCAs gadolinium is retained in the body. This includes retention in the brain and in other tissues and organs. With the linear GdCAs this can cause dose-dependent increases in T1-weighted signal intensity in the brain, particularly in the dentate nucleus, globus pallidus, and thalamus. Signal intensity increases and non-clinical data show that gadolinium is released from linear GdCAs.
Gadoxetate disodium is not metabolized.
Gd-EOB-DTPA is equally eliminated via the renal and hepatobiliary routes. The half–life of Gd-EOB-DTPA was approximately 1.0 hour.The pharmacokinetics was dose-linear up to the dose of 0.4 ml/kg (100 micromol/kg).
A total serum clearance (Cltot) of about 250 ml/min was recorded, whereas the renal clearance (Clr) corresponds to about 120 ml/min.
In accordance with the physiological changes in renal function with age, the plasma clearance of gadoxetate disodium was reduced from 210 ml/min in non-elderly subjects to 163 ml/min in elderly subjects aged 65 years and above. Terminal half-life and systemic exposure were higher in the elderly (2.3 h and 197 µmol*h/l, compared to 1.6 h and 153 µmol*h/l, respectively). The renal excretion was complete after 24 h in all subjects with no difference between elderly and non-elderly healthy subjects.
In patients with mild and moderate hepatic impairment, a slight to moderate increase in plasma concentration, half-life and urinary excretion, as well as decrease in hepatobiliary excretion have been observed in comparison to subjects with normal liver function. However, no clinically relevant differences in hepatic signal enhancement were observed. In patients with severe hepatic impairment, especially in patients with abnormally high (>3 mg/dl) serum bilirubin levels, the AUC was increased to 259 µmol*h/l compared to 160 µmol*h/l in the control group. The elimination half-life was increased to 2.6 h compared to 1.8 h in the control group. The hepatobiliary excretion substantially decreased to 5.7% of the administered dose and the hepatic signal enhancement is reduced in these patients.
In patients with end-stage renal failure the AUC increased 6-fold to about 903 µmol*h/l and the terminal half-life was prolonged to about 20 h. Hemodialysis increased the clearance of gadoxetate disodium. In an average dialysis session of about 3-hour duration, about 30% of the gadoxetate disodium dose was removed by hemodialysis starting 1 hour post injection. In addition to clearance by hemodialysis, a significant fraction of the administered gadoxetate dose is biliary excreted in these patients as shown by a mean recovery of about 50% in feces within 4 days (range 24.6 to 74.0%, n=6 patients).
Preclinical data reveal no special hazard for humans based on conventional studies of acute and subchronic toxicity, genotoxicity and contact-sensitising potential.
In telemetered conscious dogs a small and transient QT prolongation was observed at the highest dose tested of 0.5 mmol/kg, which represents 20 times the human dose. At high concentrations, Gd-EOB-DTPA blocked the HERG channel and prolonged the action potential duration in isolated guinea pig papillary muscles. This indicates a possibility that gadoxetic acid might induce QT prolongation when overdosed.
No findings have been observed in safety pharmacology studies in other organ systems.
In a rabbit embryotoxicity study, an increased number of postimplantational losses and increased abortion rate were observed after repeated administration of 2.0 mmol/kg of Gd-EOB-DTPA, representing 25.9 times (based on body surface area) or approx. 80 times (based on body weight) the recommended human dose.
In lactating rats, less than 0.5% of the intravenously administered dose (0.1 mmol/kg) of radioactively labelled gadoxetate was excreted into the breast milk. Absorption after oral administration was very low in rats with 0.4%.
Single and repeat-dose toxicity studies in neonatal and juvenile rats did not differ qualitatively from those observed in adult rats, but the juveniles are more sensitive.
Local intolerance reactions were only observed after intramuscular administration of Gd-EOB-DTPA.
No carcinogenicity studies were performed.
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