Letter to the Editor: “Macrocyclic MR contrast agents: evaluation of multiple-organ gadolinium retention in healthy rats”

Authors: Mark Hibberd, Emilio Moreno Carretero, Dustin Dunham, Paul Evans, Anand Bherwani (dr.anand.bherwani@ge.com), Paul Jones, Julie Noble.

Affiliations: Pharmaceutical Diagnostics, GE Healthcare, United States

Dear Editor in Chief,

We read with interest the article by Bussi et al. recently published in Insights into Imaging [1] and welcome any study which aims to increase the understanding of gadolinium (Gd) retention in the brain and other tissues after gadolinium-based contrast agent (GBCA) administration. The article describes a study of the measurement of gadolinium in blood and organs of rats (15/group) at a single time point 28 days after the administration of 20 human equivalent doses of 0.6 mmol/kg of gadoteridol (ProHance), gadoterate (Dotarem and Clariscan), or gadobutrol (Gadovist).

Bussi et al. report lower Gd levels in several rat tissues following gadoteridol administration than for animals administered either of the other Gd-based contrast agents (GBCAs) tested at the 28 day timepoint. However, it would be incorrect to conclude, as they do, that the lower levels of Gd for gadoteridol is indicative of more rapid clearance due to unique physio-chemical features of this GBCA that facilitate more rapid and efficient clearance. As pointed out by the authors, conclusions from the data represented must be drawn with caution as this study has only one tissue Gd measurement at a relatively early timepoint (28 days), especially when it has already been demonstrated that low levels of Gd are retained in tissue for 1 year or more following the administration of any GBCA [2,3]. As elimination curves with multiple time points are not presented, it is impossible to conclude that gadoteridol is cleared more rapidly than either of the other macrocyclic GBCAs studied. With these data, any assumptions about clearance remain speculative.

In addition, the article also suggests possible mechanisms for their findings at 28 days, based upon differences in GBCA physicochemical properties, although no experimental data that link physicochemical properties to the results are presented. Bussi et al. focuses on the relative molecular weights, ionic interactions, and number of hydrogen bonds between the Gd-ligand complex and water molecules. With respect to molecular weight, Bussi et al. state that “of the three macrocyclic molecules investigated, gadoteridol has a low molecular weight.” The molecular weights of the three GBCAs are 557.6 (gadoterate), 558.7 (gadoteridol), 604.7 (gadobutrol), and as gadoteridol lies within the range of molecular weights of the other agents it has no advantage. Moreover, no evidence is presented to establish that the trivial differences in molecular weight have any bearing on retained gadolinium and would not of themselves be expected to significantly affect diffusion or clearance of the agent.

Secondly, the authors postulate that the number of hydrogen bonds between the GBCA complex and the surrounding matrix may be related to clearance, with fewer bonds facilitating more rapid diffusion and clearance. The argument presented in the article was limited to a theoretical discussion comparing the number of hydroxyl groups in gadoteridol (one) with those in gadobutrol (three). However, the authors omit any comparison to gadoterate, which has no hydroxyl groups, and by the authors’ suggestion, should have the most rapid clearance. Regardless, the authors fail to present any evidence that small differences in the number of hydrogen bonds has any effect on GBCA retention and clearance.

Summarizing the effects of molecular weight, number of hydroxy groups and ionic interactions, the authors refer in Table 2 to parameters that do not correlate with the Gd levels they report in tissues. Gadoterate presents higher hydrophilic surface and lower solvation enthalpy values than gadobutrol but consistently has lower tissue concentrations presented in Fig 1 and Table 1. These data therefore suggest that minor differences in physicochemical properties have a minimal influence on Gd levels. Other factors known to exert a significant impact on gadolinium retention, such as differences in thermodynamic and kinetic stability [4,5], have been neglected in the authors’ discussion. Finally, Bussi et al.’s supposition that thermodynamic and kinetic stability are irrelevant to Gd retention is in stark contrast to the hypothesis developed in the body of literature published over many years [4,5].

The authors refer to the study by Jost et al. [2]. This study noted lower levels of gadolinium at 5 weeks for gadoteridol (0.19 nmol/g) than for gadobutrol (0.63 nmol/g) and gadoterate meglumine (0.54 nmol/g). However, at 26 weeks, the residual concentrations were lower for gadoterate meglumine (0.07 nmol/g) as compared to gadobutrol (0.12 nmol/g), and gadoteridol (0.12 nmol/g). At the termination of the experiment, up to 90% of gadobutrol, 94% of gadoterate meglumine and only 81% of gadoteridol was eliminated thus the clearance of gadoteridol was slower than both gadoterate and gadobutrol as tabulated by Jost et al. (2). Conclusions based solely on the Jost et al. data would then indicate that gadoteridol was the least rapidly cleared of the GBCAs tested.

In summary, the Bussi et al. study does not establish more rapid clearance of gadoteridol, as clearance was not measured. Nor does the data presented in the paper support any of the hypotheses that small differences in physicochemical properties including molecular weight, hydrogen bonding or ionicity are important factors affecting retained Gd levels after GBCA administration. Furthermore, the gadolinium levels in the brain at 52 weeks after exposure to macrocyclic GBCAs, are similar for all macrocyclic agents and close to the amount of gadolinium detected in control animals. Further studies are needed to establish the clinical relevance of microscopic brain gadolinium retention and whether any meaningful differences in clearance exists between macrocyclic agents.

References:

[1] Bussi S, Coppo A, Celeste R, et al (2020) Macrocyclic MR contrast agents: evaluation of multiple-organ gadolinium retention in healthy rats. Insights Imaging 11: 11.
[2] Jost G, Frenzel T, Boyken J, Lohrke J, Nischwitz V, Pietsch H (2019) Long-term Excretion of Gadolinium-based Contrast Agents: Linear versus Macrocyclic Agents in an Experimental Rat Model. Radiology 290(20):340-348.
[3] Lancelot E (2016) Revisiting the pharmacokinetic profiles of gadolinium-based contrast agents: differences in long-term biodistribution and excretion. Invest Radiol 51(11):691–700.
[4] McDonald RJ, Levine D, Weinreb J, et al (2018) Gadolinium Retention: A Research Roadmap from the 2018 NIH/ACR/RSNA Workshop on Gadolinium Chelates. Radiology 289(2):517-534.
[5] Frenzel T, Lengsfeld P, Schirmer H, Hütter J, Weinmann HJ (2008) Stability of gadolinium-based magnetic resonance imaging contrast agents in human serum at 37 degrees C. Invest Radiol 43(12):817–828.