Re: Chemical Structure and Stability of Gadolinium Chelates

HomeRadioGraphicsVol. 29, No. 7 PreviousNext Free AccessRe: Chemical Structure and Stability of Gadolinium ChelatesJean-Marc Idée, Marc Port, Claire CorotJean-Marc Idée, Marc Port, Claire CorotAuthor AffiliationsResearch Department, Guerbet, Aulnay-sous-Bois, BP 57400, Roissy Charles de Gaulle Cedex, France e-mail: [email protected]Jean-Marc IdéeMarc PortClaire CorotPublished Online:Nov 1 2009https://doi.org/10.1148/radiographics.29.7.0292099MoreSectionsPDF ToolsImage ViewerAdd to favoritesCiteTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinked InEmail Editor:We read with great interest the article in the January-February 2009 issue by Juluru et al (1), who discussed the link between gadolinium chelates and nephrogenic systemic fibrosis. We offer the following comments.1. In Table 3 of their article, Juluru et al (1) summarized the physicochemical characteristics of available gadolinium chelates. Gadobutrol (Gadovist; Bayer Schering Pharma, Berlin, Germany) was mistakenly described as an ionic macrocyclic agent. Gadobutrol is actually a nonionic macrocyclic agent (2), just as gadoteridol (Prohance; Bracco Diagnostics, Milan, Italy) is. The only ionic macrocyclic gadolinium chelate currently marketed is gadoterate (Dotarem; Guerbet, Villepinte, France).2. We fully agree with Juluru and co-authors that, in general, ionic agents are more stable than the nonionic molecules. We compared the kinetic stabilities of all gadolinium chelates in strictly similar conditions (pH 1.0, 25°C) and found the following dissociation half-lives (t1/2) ranked in descending order: gadoterate, 338 hours; gadobutrol, 43 hours; gadoteridol, 3.9 hours; and linear gadolinium chelates, <5 seconds (2).3. Table 3 shows t1/2 values, extrapolated to the physiologic pH 7.4 for macrocyclic gadolinium chelates, given as being more than 1000 years. This assertion is extracted from Schmitt-Willich (3). However, as rightly acknowledged by Juluru et al (1), such an extrapolation is based on certain assumptions. Specifically, it is assumed that the proton-catalyzed decomplexation of gadolinium chelates is similar at pH 7.4 and pH 1.0 (ie, in experimental conditions where H+ concentrations are dramatically different). To the best of our knowledge, this assumption has never been demonstrated. We believe, therefore, that the extrapolated t1/2 values should be considered with great caution.4. According to Juluru et al (1), stability of gadolinium chelates should be assessed differently for linear and macrocyclic agents. We believe that such an assertion is not always valid. If the time allowed to the system is long enough for an equilibrium to be reached between free Gd3+ and the chelated form, the amount of free Gd3+ released exclusively depends on conditional thermodynamic stability at pH 7.4 (log Kconditional). However, if the system does not allow such a thermodynamic equilibrium to be reached (eg, for pharmacokinetic reasons such as storage in a deep body compartment)—in other words, if earlier time points are considered—the amount of Gd3+ released depends on both thermodynamic and kinetic stabilities of gadolinium chelates (2). This general rule applies to all categories of gadolinium chelates.5. Results of several preclinical studies support the hypothesis that free gadolinium has a role in development of nephrogenic systemic fibrosis (4–6). It has been hypothesized that gadolinium chelates may be sequestered in deep compartments such as bones and that precipitated gadolinium is gradually released in the body to trigger the disease in a favorable environment (7,8). This theory and others remain to be investigated.References1 Juluru K, Vogel-Claussen J, Macura KJ, Kamel IR, Steever A, Bluemke DA. MR imaging in patients at risk for developing nephrogenic systemic fibrosis: protocols, practices, and imaging techniques to maximize patient safety. RadioGraphics 2009;29(1):9–22. Link, Google Scholar2 Port M, Idée JM, Medina C, Robic C, Sabatou M, Corot C. Efficiency, thermodynamic and kinetic stability of marketed gadolinium chelates and their possible clinical consequences: a critical review. Biometals 2008;21(4):469–490. Crossref, Medline, Google Scholar3 Schmitt-Willich H. Stability of linear and macrocyclic gadolinium based contrast agents. Br J Radiol 2007;80(955):581–585. Crossref, Medline, Google Scholar4 Sieber MA, Pietsch H, Walter J, Haider W, Frenzel T, Weinmann HJ. A preclinical study to investigate the development of nephrogenic systemic fibrosis: a possible role for gadolinium-based contrast media. Invest Radiol 2008;43(1):65–75. Crossref, Medline, Google Scholar5 Pietsch H, Lengsfeld P, Steger-Hartmann Tet al.. Impact of long-term retention of gadolinium in the rodent skin following the administration of gadolinium-based contrast agents. Invest Radiol 2009;44(4): 226–233. Crossref, Medline, Google Scholar6 Varani J, DaSilva M, Warner RLet al.. Effects of gadolinium-based magnetic resonance imaging agents on human skin in organ culture and human skin fibroblasts. Invest Radiol 2009;44(2):74–81. Crossref, Medline, Google Scholar7 Perazella MA. Tissue deposition of gadolinium and development of NSF: a convergence of factors. Semin Dial 2008;21(2):150–154. Crossref, Medline, Google Scholar8 Thakral C, Alhariri J, Abraham JL. Long-term retention of gadolinium in tissues from nephrogenic systemic fibrosis patient after multiple gadolinium-enhanced MRI scans: case report and implications. Contrast Media Mol Imaging 2007;2(4):199–205. 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