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British Journal of Radiology (2008) 81, 258-259
© 2008 British Institute of Radiology
doi: 10.1259/bjr/94141681
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Correspondence

Stability of gadolinium chelates and their biological consequences: new data and some comments

Sir,

We have read with great interest the exchange of letters between Drs Schmitt-Willich [1], Tweedle [2] and Morcos [3] regarding the biological and clinical consequences of the stability of gadolinium chelates following Dr Morcos' Commentary [4].

We believe that several of the points raised in this exchange certainly deserve to be clarified and, in certain cases, disproved, and that significant data still remain to be provided on this important subject.

Schmitt-Willich [1] rightly stresses the importance of kinetic stability, which is without doubt the main criterion to predict the fate of Gd3+ chelate and the amount of free gadolinium release either by decomplexation or by transmetallation in physiological situations, as discussed elsewhere [5–7]. Kinetic stability was first appreciated by measuring the rate of spontaneous or proton-assisted dissociation kobs of the Gd3+ complexes and their half-life (T1/2) in 0.1 M HCl (pH = 1.0) at 25°C [8]. The results obtained demonstrate that the half-lives differed dramatically: they were clearly found to be longer for macrocyclic chelates (T1/2 for gadoterate > 1 month, for gadoteridol = 3 h) than for linear chelates (T1/2 for gadopentetate = 10 min, for gadodiamide ~30 s). However, these authors reported different kobs constants for the same experiment in three successive publications [8–10], which also differ from those measured by Pulukkody [11]. Schmitt-Willich mentioned Bayer Schering's dissociation T1/2 values at pH = 1.0 for gadoteridol and gadobutrol but, unfortunately, not for gadoterate [1]. In order to be exhaustive, we measured, in a strict comparative protocol in our laboratory, the kobs and T1/2 values of the three macrocyclic compounds (Table 1Go). The values obtained demonstrate that, at pH = 1.2 and 37°C, the order of kinetic stability is gadoterate > gadobutrol > gadoteridol.


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  		Table 1. Half-life (T1/2) values of macrocyclic gadolinium complexes (commercial solutions)

 
Morcos [4] and Perazella [12] have raised the hypothesis that nephrogenic systemic fibrosis (NSF) can be the devastating consequence of in vivo decomplexation of Gd chelates. So far, the overwhelming majority of reported cases of NSF concerned the non-ionic linear chelate gadodiamide. Some unconfounded cases associated with the ionic linear chelate gadopentetate have also been reported [13] (as well as one single case with gadoteridol (Bracco, personal communication), leading to the contra-indication of gadodiamide and gadopentetate in patients with Stages 4 and 5 chronic kidney disease in Europe.

Tweedle amply quotes a study he published 12 years ago [14] and states that the results of this study "show that the non-ionic macrocycle, gadoteridol, left lower residual Gd in animals than the ionic macrocycle gadoterate" and that its conclusion (residual whole body Gd at 14 days being gadoteridol ~ gadoterate ≤ gadopentetate << gadodiamide) was made "conservatively". The choice of the latter adverb seems questionable for several reasons:

  1. The alleged difference between these two macrocyclic molecules is absolutely not emphasized in the article in question, where the compounds were regarded as being similar;
  2. The minor difference sometimes found in the % ID between these two agents is superseded by the fact that the authors only took into account the limit of detection (LOD), and not the limit of quantitation (LOQ). This is especially important for the comparison between gadoterate and gadoteridol at late time-points. Therefore, any statistical study to compare these agents is intrinsically flawed by the fact that LOQ was not taken into account. Furthermore, the authors should have made an appropriate statistical analysis (e.g. an analysis of variance (ANOVA) for repeated measures with estimation of the time x product interaction);
  3. The solutions injected in mice were not of pharmaceutical quality (dilution allegedly 1:4 in water; in fact, 1:5 according to Table 1Go);
  4. Even if the percentage of free 153Gd is negligible, we are concerned by the fact that there are no data to demonstrate that the groups were similar regarding the percentage of free 153Gd injected.

Although we believe that these flaws are not sufficient to question the obvious difference between macrocycles and gadodiamide, stating retrospectively that there were relevant differences between gadoteridol and gadoterate is simply not supported by the facts.

Tweedle also states that the macrocycles are more stable in vivo than the non-ionic linear chelates, which is absolutely true. However, it would have been more accurate to add that macrocycles are also more stable than ionic linear chelates. Tweedle omits to mention an important article [15] in which the tissue distribution of several Gd chelates, including gadoterate and the di-ionic linear chelates gadopentetate and gadobenate, were compared in mice. In that study, gadoterate was considered the reference for in vivo stability. At 24 h, the amounts of gadobenate and gadopentetate found in the liver and skeleton were clearly higher than those associated with gadoterate [15].

Physicochemical data demonstrate that the ionic macrocycle is kinetically and thermodynamically more stable than non-ionic macrocycles [5] (Table 1Go) and, a fortiori, than linear molecules. Moreover, because of their intrinsic biological variability and lack of sensitivity, the in vivo models available so far do not allow us to discriminate between macrocyclic agents. As rightly mentioned by Morcos [3], clinically relevant models, such as rats with chronic renal failure, urgently need to be investigated.

Yours etc.,

M PORT, J-M IDEE, C MEDINA, A DENCAUSSE and C COROT

Guerbet, Research Division, BP 57400, 95943 Roissy-CdG cedex, France. E-mail: marc.port{at}guerbet-group.com

Received for publication September 12, 2007. Revision received October 30, 2007. Accepted for publication December 12, 2007.

References

  1. Schmitt-Willich H. Stability of linear and macrocyclic gadolinium based contrast agents. Br J Radiol 2007;80:581–2.[Free Full Text]
  2. Tweedle MF. Stability of gadolinium chelates. Br J Radiol 2007;80:583–4.[Free Full Text]
  3. Morcos SK. Reply to Schmitt-Willich and Tweedle MF. Br J Radiol 2007;80:584–5.[Free Full Text]
  4. Morcos SK. 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? Brit J Radiol 2007;80:73–6.[Free Full Text]
  5. Idée JM, Port M, Raynal I, Schaefer M, Le Greneur S, Corot C. Clinical and biological consequences of transmetallation induced by contrast agents for magnetic resonance imaging : a review. Fundam Clin Pharmacol 2006;20:563–76.[CrossRef][Medline]
  6. Kumar K. Macrocyclic polyamino carboxylate complexes of Gd(III) as magnetic resonance imaging contrast agents. J Alloys Comp 1997;249:163–72.[CrossRef]
  7. Caravan P, Ellison JJ, McMurry TJ, Lauffer RB. Gadolinium(III) chelates as MRI contrast agents: structure, dynamics, and applications. Chem Rev 1999;99:2293–352.[CrossRef][Medline]
  8. Tweedle MF. Physicochemical properties of gadoteridol and other magnetic resonance contrast agents. Invest Radiol 1992;27(Suppl:1)S2–6.[CrossRef][Medline]
  9. Kumar K, Tweedle MF. Macrocyclic polyaminocarboxylate complexes of lanthanides as magnetic resonance imaging contrast agents. Pure and Appl Chem 1993;65:515–20.[CrossRef]
  10. Wedeking P, Kumar K, Tweedle MF. Dissociation of gadolinium chelates in mice: relationship to chemical characteristics. Magn Reson Imaging 1992;10:641–8.[CrossRef][Medline]
  11. Pulukkody KP, Norman TJ, Parker D, Royle L, Broan CJ. Synthesis of charged and uncharged complexes of gadolinium and yttrium with cyclic polyazaphosphinic acid ligands for in vivo applications. J Chem Soc Perkin Trans 1993;2:605–20.
  12. Perazella MA. Nephrogenic systemic fibrosis, kidney disease, and gadolinium: is there a link? Clin J Am Soc Nephrol 2007;2:200–2.[Free Full Text]
  13. Kanal E, Barkovich AJ, Bell C, Borgstede JP, Bradley WG Jr, Froelich JW, et al. ACR guidance document for safe MR practice: 2007. Am J Roentgenol 2007;188:1–27.[Free Full Text]
  14. Tweedle MF, Wedeking P, Kumar K. Biodistribution of radiolabeled, formulated gadopentetate, gadoteridol, gadoterate and gadodiamide in mice and rats. Invest Radiol 1995;30:372–80.[CrossRef][Medline]
  15. Harrison A, Walker CA, Pereira KA, Parker D, Royle L, Pulukkody K, et al. Hepato-biliary and renal excretion in mice of charged and neutral gadolinium complexes of cyclic tetra-aza-phosphinic and carboxylic acids. Magn Reson Imaging 1993;11:761–70.[CrossRef][Medline]




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