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Gd accumulation in tissues of healthy mice upon repeated administrations of Gd-based contrast agents

Eliana Gianolio¹, Enza Di Gregorio¹, Giuseppe Ferrauto¹, and Silvio Aime¹

¹Molecular Biotechnologies and Health Science, University of Torino, Torino, Italy

Synopsis

GBCAs are routinely used in many clinical MRI protocols, their high stability should ensure that the Gd-complexes are excreted intact without side effects. Recently, it was reported that tiny amounts of Gd3+ may be retained in the brain of patients. The aim of this study was to investigate, in an animal model, the in vivo fate of Gadoteridol and Gadodiamide extending the investigation of Gd retention to other body tissues besides brain. Several administration protocols differing for i) the number of total doses, ii) the frequency of the administrations and iii) the sacrifice time after the last administration, were compared.

Introduction

Recently, a renewed interest on the possibility that Gadolinium Based Contrast Agents (GBCAs) may cause adverse effects, came out because a number of studies reported the occurrence of Gadolinium retention in the brain of patients that have been previously administered with multiple doses of GBCAs.1 The aim of this study was to use a validated animal model to compare different GBCAs i.v. administration schemes in order to assess in which way they affect the accumulation and distribution of Gd-containing species in the body tissues of healthy mice.

Methods

Gadodiamide and Gadoteridol have been compared. The accumulation of Gd in several tissues/organs (cerebrum, cerebellum, spleen, liver, kidneys, eyes, skin, bone and muscle) has been assessed by ICP-MS upon administration of the GBCAs i) at different times after the last administration (3 weeks or 3 months), ii) when one, three or twelve doses (0.1 mmol/Kg) of GBCA were administered and iii) when administrations were made every two weeks.

Results

Gd was found in all tissues after the administration of Gadodiamide. Conversely, in the case of Gadoteridol, Gd was detected only in spleen, kidneys, liver and bone. For both GBCAs the amount of Gd depends on the number of administered doses. The amounts of Gd found in spleen, liver and kidneys markedly decrease upon increasing the time that has passed after the last administration, whereas, in the case of Gadodiamide, the decrease of Gd accumulated in bone, cerebrum and cerebellum appears to occur at a much slower rate. Overall, areas of long term deposition appear to be bone and spleen for both GBCAs.

Discussion and Conclusion

The herein reported results show that, in the case of Gadodiamide, significant amounts of Gd are found in all the investigated organs, even when administered at low dose. Conversely, in the case of Gadoteridol, Gd retention appears limited to some organs, only upon repeated administrations. In conclusion, our findings demonstrate that intravenous multiple administrations of GBCAs is associated with extensive multiorgan depositions which is reduced but not eliminated by the use of the macrocyclic Gadoteridol as well as by adopting reduced and/or less frequent dosing.

Acknowledgements

The study was funded by Progetto di Ateneo Compagnia di San Paolo (CSTO160182). E.D.G and G.F. were supported by FIRC-AIRC (Fondazione Italiana per la Ricerca sul Cancro AIRC) fellowships.

References

Gulani V, Calamante F, Shellock FG, et al. Gadolinium deposition in the brain: summary of evidence and reccomendations Lancet Neurol. 2017;16:564‐570.

Figures

Amounts of retained Gd in selected organs after 12 injections of Gadodiamide or Gadoteridol (0.1 mmoles/Kg) three times weekly. The sacrifice time was setted at 3 weeks or 3 months after the last administration.

Proc. Intl. Soc. Mag. Reson. Med. 26 (2018)

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