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Identification and quantification of potential metabolites of Gd-based contrast agents


Magnetic resonance imaging (MRI) has become an indispensable method in medical diagnostics during the last 30 years and revolutionized clinical imaging by allowing for the generation of non-invasive tomograms of the body. Almost every third examination worldwide is enhanced by application of contrast agents, nowadays mainly based on gadolinium complexes. Because free ionic Gd is toxic, it is complexed with polyamino-carboxylic acid chelating agents. Because of their high thermodynamic stability, the Gd-based complexes were regarded as highly secure and stable pharmaceuticals.

Nephrogenic systemic fibrosis (NSF) or
nephrogenic fibrosing dermopathy is a
rare and serious syndrome that involves
fibrosis of skin, joints, eyes, and internal

However, in 2000, a new disease called nephrogenic systemic fibrosis (NSF) was described for the first time. NSF is a severe disabling fibrosing condition and is characterized by symptoms such as extensive thickening and hardening of the skin and inner organs. The disease is incurable up to now and in most cases led to the death of the patients. NSF is only observed for patients with advanced chronic kidney disease or acute renal failure who underwent an MRI examination enhanced by Gd-based contrast agents. In 2010, US FDA announced a warning to minimize the risk for patients (see the news below). The pathogenesis of NSF remains unclear, but many researchers speculated that the stability of the Gd-based contrast agents is insufficient regarding the prolonged retention caused by kidney failure.

The new studies:
The research group headed by Uwe Karst (University of Munster) recently published further results from their ongoing studies on the metabolism of Gd-based contrast agents. The new results were obtained during the work of Lena Telgmann on her Doctorial Thesis and have been published in the Journal of Chromatography A and in Analytical and Bioanalytical Chemistry (see below). These studies try to answer the question, whether toxic gadolinium can be release from the Gd-based contrast agents under physiologic conditions. Two different possibilities were considered: destabilization of the complex through oxidative degradation of the ligands and release of Gd from the complex through transmetalation.

Using an electrochemical cell coupled to ESI-MS, the researchers tried to find out, whether metabolic reactions could compromise the stability of the Gd-complex. An electrochemical cell was used as a model to mimic oxidative phase I metabolism catalyzed by enzymes of the cytochrome P450 (CYP) superfamily as the main route of elimination of xenobiotic substances. Using this approach, it could be shown that N-dealkylation reactions occur that most likely reduce the stability of the Gd complex in vivo.

In a second study, the hyphenated technique of HPLC-ESI-MS was used to study the stability of Gd-complexes in presence of iron. While the Gd-complexes are thermo-dynamically very stable, the related Fe-complexes are even more stable.  To allow the detection of very small amounts of Fe-DTPA down to 50 nmol/L, the LC system was coupled to an Exactive Orbitrap electrospray ionization mass spectrometer. In vitro experiments revealed the formation of Fe-DTPA in blood plasma samples with Gd-DTPA and Fe(III) citrate. Analysis after different incubation times of the sample showed that the exchange of the metal ions is significantly dependent on time. Transmetalation either with endogenous Fe (II)/Fe(III) ions or with parenteral Fe supplements with Gd-DTPA could not be proven under the applied conditions.  The macrocyclic complex Gd-DOTA proved to be even more stable, so that no transmetalation were observed with neither of the Fe species.

The behavior of Fe(III) citrate indicates that a transmetalation of accessible Fe(III) from the labile iron pool, which has been detected in dialysis patients after administration of parenteral Fe supplements, may be possible with Gd-DTPA. The results further indicate that transmetalation reactions may be a trigger for the development of NSF, if free Fe(III) ions are accessible during a prolonged dwell time of Gd complexes with linear ligands in the patient's body.

The original studies:

Lena Telgmann, Helene Faber, Sandra Jahn, Daniel Melles, Hannah Simon, Michael Sperling, Uwe Karst, Identification and quantification of potential metabolites of Gd-based contrast agents by electrochemistry/separations/mass spectrometry, J. Chromatography A, 1240 (2012) 147- 155. doi: 10.1016/j.chroma.2012.03.088

Lena Telgmann, Christoph A. Wehe, Jens Künnemeyer, Ann-Christin Bülter, Michael Sperling, Uwe Karst, Speciation of Gd-based MRI contrast agents and potential products of transmetalation with iron ions or parenteral iron supplements, Anal. Bioanal. Chem., 404 (2012) 2133-2141. DOI 10.1007/s00216-012-6404-x

Related Studies:

Soma Sanyal, Peter Marckmann, Susanne Scherer, Jerrold L. Abraham, Multiorgan gadolinium (Gd) deposition and fibrosis in a patient with nephrogenic systemic fibrosis—an autopsy-based review, Nephrol. Dial. Transplant., 11 (2011) 1–11. doi: 10.1093/ndt/gfr085

Charu Thakral, Jerrold L. Abraham, Gadolinium-Induced Nephrogenic Systemic Fibrosis Is Associated with Insoluble Gd Deposits in Tissues: In Vivo Transmetallation Confirmed by Microanalysis, J. Cutan Pathol., 36 (2009) 1244–1254. doi: 10.1111/j.1600-0560.2009.01283.x

J.L. Abraham, C. Thakral, L. Skov, K. Rossen, P. Marckmann, Dermal inorganic gadolinium concentrations: evidence for in vivo transmetallation and long-term persistence in nephrogenic systemic fibrosis, Br. J. Dermatol., 158 (2008) 273–280.  DOI: 10.1111/j.1365-2133.2007.08335.x

Jens Künnemeyer, Lydia Terborg, Sascha Nowak, Andy Scheffer, Lena Telgmann, Faruk Tokmak, Andreas Günsel, Gerhard Wiesmüller, Stephan Reichelt, Uwe Karst, Speciation Analysis of Gadolinium-Based MRI Contrast Agents in Blood Plasma by Hydrophilic Interaction Chromatography/Electrospray Mass Spectrometry, Anal. Chem. , 80/21 (2008) 8163-8170. doi: 10.1021/ac801264j

Clark D. Wiginton, Brent Kelly, Aytekin Oto, Mary Jesse, Patricia Aristimuno, Randy Ernst, Gregory Chaljub, Gadolinium-Based Contrast Exposure, Nephrogenic Systemic Fibrosis, and Gadolinium Detection in Tissue, Am. J. Roentgenol., 190 (2008) 1060-1068. DOI:10.2214/AJR.07.2822

S. Swaminathan, W.A. High, J. Ranville, T.D. Horn, K. Hiatt, M. Thomas, H.H. Brown, S.V. Shah, Cardiac and vascular metal deposition with high mortality in nephrogenic systemic fibrosis, Kidney International, 73 (2008) 1413–1418. doi: 10.1038/ki.2008.76

Marc Port, Jean-Marc Idée, Christelle Medina, Caroline Robic, Monique Sabatou, Claire Corot, Efficiency, thermodynamic and kinetic stability of marketed gadolinium chelates and their possible clinical consequences: a critical review, BioMetals, 21 (2008) 469-490. DOI: 10.1007/s10534-008-9135-x

Thomas Frenzel, Philipp Lengsfeld, Heiko Schirmer, Joachim  Hütter, Hanns-Joachim Weinmann, Stability of Gadolinium-Based Magnetic Resonance Imaging Contrast Agents in Human Serum at 37°C, Invest. Radiol., 43/12 (2008) 817.

 Petr Hermann, Jan Kotek, Vojtech Kubícek, Ivan Lukes, Gadolinium(III) complexes as MRI contrast agents: ligand design and properties of the complexes, Dalton Trans., (23)    (2008) 3027-3047. DOI: 10.1039/b719704g

S.K. Morcos, Nephrogenic systemic fibrosis following the administration of extracellular gadolinium based contrast agents: is the stability of the contrast agent molecule an important factor in the pathogenesis of this condition?, Br. J. Radiol., 80 (2007) 73–76. DOI: 10.1259/bjr/17111243

Jean-Marc Idée, Marc Port, Isabelle Raynal, Michel Schaefer, Soizic Le Greneur, Claire Corot, Clinical and biological consequences of transmetallation induced by contrast agents for magnetic resonance imaging: a review, Fundamental & Clinical Pharmacology 20 (2006) 563–576. doi: 10.1111/j.1472-8206.2006.00447.x

Thomas Grobner, Gadolinium – a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis?, Nephrol. Dial. Transplant., 21 (2006) 1104–1108. doi: 10.1093/ndt/gfk062

Peter Marckmann, Lone Skov, Kristian Rossen, Anders Dupont, Mette Brimnes Damholt, James Goya Heaf, Henrik S. Thomsen, Nephrogenic Systemic Fibrosis: Suspected Causative Role of Gadodiamide Used for Contrast-Enhanced Magnetic Resonance Imaging, J. Am. Soc. Nephrol., 17 (2006) 2359–2362. doi: 10.1681/ASN.2006060601

Valeria Loreti, Jörg Bettmer, Determination of the MRI contrast agent Gd-DTPA by SEC-ICP-MS, Anal. Bioanal. Chem., 379/7-8 (2004) 1050-1054. DOI: 10.1007/s00216-004-2700-4

Ernö Brücher, Kinetic Stabilities of Gadolinium(III) Chelates Used as MRI Contrast Agents, Top. Curr. Chem., 221 (2002) 103-122. doi: 10.1007/3-540-45733-X_4

S. Laurent, L. Vander Elst, F. Copoix, R.N. Muller, Stability of MRI paramagnetic contrast media: A proton relaxometric protocol for transmetallation assessment, Invest. Radiol., 36 (2001) 115–122.

Josette Behra-Miellet, Gilbert Briand, Mostafa Kouach, Bernard Gressier, Micheline Cazin, Jean-Claude Cazin, On-Line HPLC-Electrospray Ionization Mass Spectrometry: a Pharmacological Tool for Identifying and Studying the Stability of Gd3+ Complexes Used as Magnetic Resonance Imaging Contrast Agents, Biomed. Chromatogr. 12, 21–26, (1998). doi: 10.1002/(SICI)1099-0801(199801/02)12:1<21::AID-BMC714>3.0.CO;2-Z

Claire Corot, Jean-Marc Idee, Anne-Marie Hentsch, Robin Santus, Catherine Mallet,     Valérie Goulas, Bruno Bonnemain, Dominique Meyer, Structure-activity relationship of macrocyclic and linear gadolinium chelates: Investigation of transmetallation effect on the zinc-dependent metallopeptidase angiotensin-converting enzyme, J. Magn. Reson. Imaging, 8/3 (1998) 695–702. DOI: 10.1002/jmri.1880080328

C. Corot, A.M. Hentsch, L. Curtelin, Interaction of Gadolinium Complexes with Metal-Dependent Biological Systems, Invest. Radiol., 29/sup.2 (1994) S164–167.

M.F. Tweedle, J.J. Hagan, K. Kumar, S. Mantha, C.A. Chang, Reaction of gadolinium chelates with endogenously available ions, Magnem. Resonance Imaging, 9 (1991) 409-415. doi: 10.1016/0730-725X(91)90429-P

Related EVISA Resources

Link Database: Toxicity of Gadolinium compounds
Link database: Use of Gadolinium in pharmaceuticals
Materials Database: Gadolinium Materials
Brief summary: ICP-MS - A versatile detection system for speciation analysis
Brief summary: ESI-MS: The tool for the identification of chemical species
Brief summary: LC-ICP-MS - The most often used hyphenated system for speciation analysis
Brief summary: Speciation analysis for the study of metallodrugs and their biomolecular interactions

Related EVISA News

October 18, 2012: The behavior of Gd-based contrast agents during wastewater treatment
September 15, 2010: US FDA Announces Gadolinium-Based MRI Contrast Agent Warning
March 25, 2010: Publication on the separation of Gd-based contrast agents awarded
May 4, 2009: Gadolinium speciation analysis in search for the cause of nephrogenic systemic fibrosis (NSF)
April 17, 2009: Gadolinium-based MRI contrast agents found intact in the outlet of a waste water treatment plant

last time modified: October 29, 2012


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