Gd accumulation in tissues of healthy mice upon repeated administrations of Gadodiamide and Gadoteridol

The aim of this work was to investigate, by five different administration protocols, the impact of the dosage, the time passed after the last injection and the frequency of injections, on accumulation and distribution of Gd-containing species in the body tissues of healthy mice upon repeated injections of Gadolinium Based Contrast Agents (GBCAs). Gadodiamide and Gadoteridol have been compared. The amount of Gd retained 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 three weeks or three months after the last administration, ii) when one, three or twelve doses of GBCA were administered and iii) when administrations were made every two weeks. 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. 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 found 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. In conclusion, our findings demonstrate that intravenous multiple administrations of GBCAs is associated with extensive multiorgan retention which is reduced but not eliminated by the use of the macrocyclic Gadoteridol as well as by adopting reduced and/or less frequent dosing.