Pharmacokinetics of Gadomer-17, a new dendritic magnetic resonance contrast agent

Misselwitz, Bernd; Schmitt‐Willich, Heribert; Ebert, Wolfgang; Frenzel, Thomas; Weinmann, Hanns‐Joachim

doi:10.1007/bf02668094

Cited by 147 publications

(90 citation statements)

References 24 publications

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“…[23] The gadolinium concentrations in blood were converted to plasma concentrations by assuming a hematocrit value of 0.53. [44] Biodistribution: Adult Wistar rats (n = 3/group, 273 g AE 9 g, Harlan, The Netherlands) were anesthetized and injected with the contrast agents, as described above. Sixty minutes after injection, the animals were sacrificed and samples of liver, kidneys, heart, lungs, and spleen were collected for evaluation of the gadolinium content.…”

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confidence: 99%

Synthesis, Characterization, and Pharmacokinetic Evaluation of a Potential MRI Contrast Agent Containing Two Paramagnetic Centers with Albumin Binding Affinity

Parac‐Vogt

Kimpe

Laurent

et al. 2005

Chemistry A European J

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A dinuclear gadolinium(III) complex of an amphiphilic chelating ligand, containing two diethylenetriamine-N,N,N',N'',N''-pentaacetate (DTPA) moieties bridged by a bisindole derivative with three methoxy groups, has been synthesized and evaluated as a potential magnetic resonance imaging (MRI) contrast agent. Nuclear magnetic relaxation dispersion (NMRD) measurements indicate that at 20 MHz and 37 degrees C the dinuclear gadolinium(III) complex has a much higher relaxivity than [Gd(DTPA)] (6.8 vs 3.9 s(-1) mmol(-1)). The higher relaxivity of the dinuclear gadolinium(III) complex can be related to its reduced motion and larger rotational correlation time relative to [Gd(DTPA)]. In the presence of human serum albumin (HSA) the relaxivity value of the noncovalently bound dinuclear complex increases to 15.2 s(-1) per mmol of Gd3+, due to its relatively strong interaction with this protein. The fitted value of the binding constant to HSA (Ka) was found to be 10(4) M(-1). Because of its interaction with HSA, the dinuclear complex exhibits a longer elimination half-life from the plasma, and a better confinement to the vascular space compared to the commercially available [Gd(DTPA)] contrast agent. Transmetalation of the dinuclear gadolinium(III) complex by zinc(II) has been investigated. Biodistribution studies suggest that the complex is excreted by the renal pathway, and possibly by the hepatobiliary route. In vivo studies indicated that half of the normal dose of the gadolinium(III) complex enhanced the contrast in hepatic tissues around 40 % more effectively than [Gd(DTPA)]. The dinuclear gadolinium(III) complex was tested as a potential necrosis avid contrast agent (NACA), but despite the binding to HSA, it did not exhibit necrosis avidity, implying that binding to albumin is not a key parameter for necrosis-targeting properties.

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confidence: 99%

Synthesis, Characterization, and Pharmacokinetic Evaluation of a Potential MRI Contrast Agent Containing Two Paramagnetic Centers with Albumin Binding Affinity

Parac‐Vogt

Kimpe

Laurent

et al. 2005

Chemistry A European J

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“…The gadolinium-based MR blood pool contrast agent Gadomer (Schering AG, Berlin), which is currently undergoing clinical development for MRA and perfusion imaging, was used in this study [14]. Gadomer consists of a water-soluble 24-gadolinium dendrimer with a molecular weight of 17 kDa.…”

Section: Contrast Materialsmentioning

confidence: 99%

3D pulmonary perfusion MRI and MR angiography of pulmonary embolism in pigs after a single injection of a blood pool MR contrast agent

et al. 2004

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The purpose of this study was to assess the feasibility of contrast-enhanced 3D perfusion MRI and MR angiography (MRA) of pulmonary embolism (PE) in pigs using a single injection of the blood pool contrast Gadomer. PE was induced in five domestic pigs by injection of autologous blood thrombi. Contrast-enhanced first-pass 3D perfusion MRI (TE/TR/FA: 1.0 ms/2.2 ms/40 degrees; voxel size: 1.3 x 2.5 x 4.0 mm3; TA: 1.8 s per data set) and high-resolution 3D MRA (TE/TR/FA: 1.4 ms/3.4 ms/40 degrees; voxel size: 0.8 x 1.0 x 1.6 mm3) was performed during and after a single injection of 0.1 mmol/kg body weight of Gadomer. Image data were compared to pre-embolism Gd-DTPA-enhanced MRI and post-embolism thin-section multislice CT (n = 2). SNR measurements were performed in the pulmonary arteries and lung. One animal died after induction of PE. In all other animals, perfusion MRI and MRA could be acquired after a single injection of Gadomer. At perfusion MRI, PE could be detected by typical wedge-shaped perfusion defects. While the visualization of central PE at MRA correlated well with the CT, peripheral PE were only visualized by CT. Gadomer achieved a higher peak SNR of the lungs compared to Gd-DTPA (21 +/- 8 vs. 13 +/- 3). Contrast-enhanced 3D perfusion MRI and MRA of PE can be combined using a single injection of the blood pool contrast agent Gadomer.

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“…A promising clinical candidate is Gadomer (formerly termed Gadomer 17) which is currently developed as a blood pool agent for magnetic resonance imaging [12,13]. Figure 1 shows the structure of the target substance Gadomer 24 and of selected related dendrimers, which may be present in Gadomer due to degradation processes or as synthesis byproducts.…”

Section: Introductionmentioning

confidence: 99%

Capillary electrophoresis for the characterization of the complex dendrimeric contrast agent Gadomer

Vetterlein¹,

Büche²,

Hildebrand³

et al. 2006

Electrophoresis

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A CE method for the characterization of the complex dendrimeric contrast agent Gadomer has been developed and validated. The method was capable of separating the target substance Gadomer 24 from related dendrimers containing amino or carboxyl functions and from impurities of lower molecular weight. The compounds were separated in a fused-silica capillary. The optimized BGE consisted of 15 mM sodium phosphate, pH 6.3, containing 0.5 mM hexadecyltrimethylammonium bromide. The assay was validated with regard to linearity, specificity, accuracy, LOD and LOQ as well as robustness according to the guidelines of the International Conference on Harmonization. The method allows the determination of the purity and stability of the drug substance Gadomer as well as its injectable formulation. On the basis of the present study, a strategy for the quality assurance and quality control of the complex dendrimeric drug candidate Gadomer may be devised. The method may therefore serve as a key component in a set of analytical methodologies designed to assure and control the reproducible quality and safety of this innovative product. To the best of our knowledge, this is the first work reporting a validated method for the characterization, impurity profiling, and stability testing of a dendrimeric agent designed for clinical use.

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Pharmacokinetics of Gadomer-17, a new dendritic magnetic resonance contrast agent

Abstract: Gadomer-17 is a promising new MR contrast medium that has an intravascular distribution and a rapid renal elimination.

Cited by 147 publications

References 24 publications

Synthesis, Characterization, and Pharmacokinetic Evaluation of a Potential MRI Contrast Agent Containing Two Paramagnetic Centers with Albumin Binding Affinity

Synthesis, Characterization, and Pharmacokinetic Evaluation of a Potential MRI Contrast Agent Containing Two Paramagnetic Centers with Albumin Binding Affinity

3D pulmonary perfusion MRI and MR angiography of pulmonary embolism in pigs after a single injection of a blood pool MR contrast agent

Capillary electrophoresis for the characterization of the complex dendrimeric contrast agent Gadomer

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