Reply to the Letter to the Editor: “Macrocyclic MR contrast agents: evaluation of multiple-organ gadolinium retention in healthy rats”
Authors: Simona Bussi, Federico Maisano, Miles A. Kirchin, Fabio Tedoldi
Affiliations: Bracco Imaging SpA, Milan, Italy
Dear Editor in Chief,
After reading with great interest the Letter to the Editor by Hibberd et al.  regarding our publication on gadolinium (Gd) levels in rat tissues at 28 days after contrast administration , we stand firmly behind our conclusion and those of others  that significantly lower levels of Gd are retained in brain and body tissues of rats in the first weeks and months after exposure to gadoteridol [2, 4-6], and that these lower levels of Gd are due to more rapid diffusion and clearance ascribable to more favorable physicochemical properties of the gadoteridol molecule . Our study not only supports and extends the results of our initial comparative study in animals  but also the results of others that have demonstrated significantly lower levels of retained Gd after administration of gadoteridol compared to other macrocyclic gadolinium-based contrast agents (GBCAs) in the first days  and weeks  after exposure.
In their letter, Hibberd et al.  state that it is incorrect to conclude that the lower levels of Gd reported for gadoteridol are indicative of more rapid clearance since the study has only one tissue Gd measurement at a relatively early timepoint (28 days). They go on to suggest that since 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. Previously, Jost et al  have shown that the amount of Gd retained in the cerebellum and pons after injection of identical doses (1.8 mmol/kg bodyweight) of GBCAs is similar at 24 hours post-injection indicating that all the tested GBCAs cross the blood-CSF barrier to an almost identical extent. Subsequently, these same authors determined Gd levels in rat tissues at 5, 26 and 52 weeks after eight injections of GBCAs over 2 weeks (1.8 mmol/kg per injection) and found that whereas the Gd levels at 26 and 52 weeks were roughly similar, markedly lower levels of Gd were retained in rat cerebellum at 5 weeks after the administration of gadoteridol (0.19 nmol/g) than after administration of gadobutrol (0.63 nmol/g) and gadoterate meglumine (0.54 nmol/g) . Given that all available evidence [2, 4-6] indicates that differences in Gd elimination kinetics in rats are most pronounced during a 1 to 5-week wash-out period following GBCA administration, we have recently performed a comparison of Gd levels retained in rat tissues at 1, 2, 3 and 5 weeks after administration of gadoteridol, gadobutrol and gadoteric acid and confirmed the levels of retained Gd in brain are significantly lower after gadoteridol administration at all the tested timepoints (Bracco; data under publication).
Hibberd et al.  also refer to the percentage of elimination found by Jost et al.  at the termination of their experiment (90% of gadobutrol, 94% of gadoteric acid and 81% of gadoteridol) and claim that this indicates that gadoteridol is the least rapidly cleared of the GBCAs tested. However, this assertion is fundamentally flawed and misleading. As reported by Jost et al.  these values represent the percentage eliminated of the gadolinium concentration present at 5 weeks – not of the gadolinium present at the end of the dosing period. At 5 weeks the Gd concentration determined after gadoteridol administration was only approximately one third of the Gd concentrations determined for gadobutrol and gadoteric acid. Since the tissue Gd concentrations were similar for all the tested macrocyclic GBCAs at 52 weeks, the lowest elimination percentage between 5 and 52 weeks was observed for gadoteridol simply because the Gd level at 5 weeks was the lowest for gadoteridol due to a greater proportion of Gd having already been eliminated by that time.
Additionally, Hibberd et al.  refer to our discussion of GBCA physicochemical properties to explain the observed differences in Gd clearance. In discussing each physicochemical property individually, they seemingly willfully disregard our hypothesis and those of others  that it is the combination of properties that influences elimination rather than any one property alone. For example, Hibberd et al.  focus on molecular weight, taking our discussion out of context to suggest that we believe that molecular weight alone might be responsible for differences in clearance. As Hibberd et al.  note, molecular weight differences between the macrocyclic GBCAs are small and unlikely to impact diffusion or clearance. Our article does not claim that the molecular weight of gadoteridol alone would confer any preferential properties for Gd clearance. Likewise, Hibberd et al.  address the issue of hydrogen bonds between the GBCA complex and the surrounding matrix, focusing on our suggestion that fewer hydrogen bonds would facilitate more rapid diffusion and clearance. They argue that gadoteric acid should have the most rapid clearance because gadoteric acid has no hydroxyl groups while gadoteridol has one and gadobutrol three. Unfortunately, Hibberd et al.  fail to address our discussion of the possible role of ionic interactions on diffusion and clearance and the fact that gadoteric acid is ionic while gadoteridol and gadobutrol are not. While the absence of hydroxyl groups might favor gadoteric acid diffusion and clearance, the likely ionic interactions with the surrounding matrix might inhibit it, thereby leading to slower diffusion and clearance. Of the three macrocyclic GBCAs, the combination of physicochemical properties would appear to be most favorable for gadoteridol thus explaining its more rapid diffusion and clearance in the early days and weeks after administration.
Finally, Hibberd et al.  refer to differences in thermodynamic and kinetic stability as factors exerting a significant impact on Gd retention and claim that this is neglected in our study. The two articles cited [8, 9] primarily address differences between linear and macrocyclic GBCAs, focusing on class-based differences in chelate stability in terms of the potential for Gd release and retention. To our knowledge there are no reports of differences in macrocyclic GBCA stability affecting the amount of Gd retained. Indeed, the half-life of dissociation of all the macrocyclic GBCAs exceeds 1900 years rendering meaningless all discussion of stability affecting Gd retention.
To summarize, we stand by our conclusion and those of others  that small differences in the physicochemical properties of GBCAs have meaningful impact on the diffusion and clearance of Gd from rat tissues in the first weeks/months after administration.
 Hibberd M, Carretero EM, Dunham D, et al. (2020) Letter to the Editor: “Macrocyclic MR contrast agents: evaluation of multiple-organ gadolinium retention in healthy rats”. Insights Imaging. Available at: Blog – Insights into Imaging (i3-journal.org) (Accessed January 07, 2021).
 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.
 Aime S (2019) Differences in Molecular Structure Markedly Affect GBCA Elimination Behavior. Radiology 291:267-268.
 Bussi S, Coppo A, Botteron C, et al. (2018) Differences in gadolinium retention after repeated injections of macrocyclic MR contrast agents to rats. J Magn Reson Imaging 47:746–752.
 McDonald RJ, McDonald JS, Dai D, et al (2017) Comparison of Gadolinium Concentrations within Multiple Rat Organs after Intravenous Administration of Linear versus Macrocyclic Gadolinium Chelates. Radiology 285:536-545.
 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 290:340-348.
 Jost G, Frenzel T, Lohrke J, et al. Penetration and distribution of gadolinium-based contrast agents into the cerebrospinal fluid in healthy rats: a potential pathway of entry into the brain tissue. Eur Radiol (2017) 27:2877–2885.
 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 289:517-534.
 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°C. Invest Radiol 43:817–828.