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Background The use of gadolinium-based contrast agents (GBCAs) is linked to gadolinium retention in the skeleton of healthy individuals. The mechanism of gadolinium incorporation into bone tissue is not fully understood and requires spatially resolved analysis to locate the gadolinium. Purpose To compare the quantitative distribution of gadolinium retained over time in rodent femur following the administration of gadodiamide and gadobutrol at three different time points. Materials and Methods In this animal study conducted between May 2018 and April 2020, 108 9-week-old healthy rats were repeatedly injected with either gadodiamide, gadobutrol, or saline solution and were killed 1, 3, or 12 months after the last injection. The femurs of six female and six male rats per each group and time point were collected. Quantitative elemental imaging of gadolinium in longitudinal thin sections was performed on one sample per sex with use of laser ablation inductively coupled plasma mass spectrometry (ICP-MS). Gadolinium concentration was determined with use of ICP-MS on the samples of all animals (six per group). Mann-Whitney U tests were applied on pairwise comparisons to determine potential sex effect and GBCA effect on gadolinium concentrations. Results The highest gadolinium retention was observed in the gadodiamide group (concentration, 97-200 nmol · g -1 ), exceeding the mean concentration in the gadobutrol group (6.5-17 nmol · g -1 ). However, the gadolinium distribution pattern was similar for both contrast agents, showing prominent gadolinium retention at endosteal surfaces, in the bone marrow, and in small tissue pores. Gadolinium distribution in cortical bone changed over time, initially showing a thin rim of higher concentration close to the periosteum, which appeared to grow wider and move toward the interior of the femur over 1 year. Conclusion For both gadolinium-based contrast agents, gadolinium retention in rat bone was initially located close to the periosteum and bone cavities and changed with bone remodeling processes. The relevance to long-term storage of gadolinium in humans remains to be determined. © RSNA, 2022 Online supplemental material is available for this article.

Background Safety concerns caused by gadolinium retention call for the development of high-relaxivity gadolinium-based contrast agents (GBCAs) allowing minimal dosing. Purpose To investigate brain gadolinium retention in healthy rats after exposure to gadopiclenol (Elucirem, Guerbet; macrocyclic GBCA) compared with gadobutrol (Gadovist or Gadavist, Bayer; macrocyclic GBCA) and gadodiamide (Omniscan, GE Healthcare; linear GBCA) over 1 year. Materials and Methods In this study conducted between May 2018 and April 2020, 9-week-old healthy Sprague Dawley rats received five injections of either gadopiclenol, gadobutrol, or gadodiamide (2.4 mmol of gadolinium per kilogram of body weight for each), or saline (control animals) over a period of 5 weeks. Rats were randomly assigned to different groups (six female and six male rats per group). MRI examinations were performed before euthanasia at 1, 3, 5, or 12 months after the last injection. Brains were sampled to determine the total gadolinium content via inductively coupled plasma mass spectrometry (ICP-MS), to characterize gadolinium species with size exclusion chromatography (SEC)-ICP-MS, and to perform elemental mapping with laser ablation (LA)-ICP-MS. Mann-Whitney tests were performed on pairwise comparisons of the same time points. Results For both macrocyclic agents, no T1 signal hyperintensities were observed in the cerebellum, and approximately 80% of gadolinium washout was found between 1 month (gadobutrol, 0.30 nmol/g; gadopiclenol, 0.37 nmol/g) and 12 months (gadobutrol, 0.062 nmol/g; gadopiclenol, 0.078 nmol/g). After 12 months, only low-molecular-weight gadolinium species were detected in the soluble fraction. Gadodiamide led to significantly higher gadolinium concentrations after 1 month in the cerebellum (gadodiamide, 2.65 nmol/g; P < .001 vs both macrocyclics) combined with only 15% washout after 12 months (gadodiamide, 2.25 nmol/g) and with gadolinium detected bound to macromolecules. Elemental bioimaging enabled visualization of gadolinium deposition patterns colocalized with iron. Conclusion Gadopiclenol and gadobutrol demonstrated similar in vivo distribution and washout of gadolinium in the healthy rat brain, markedly differing from gadodiamide up to 12 months after the last injection. © RSNA, 2022 Online supplemental material is available for this article .

Purpose To compare the long-term brain elimination kinetics and gadolinium species in healthy rats after repeated injections of the contrast agents gadodiamide (a linear contrast agent) or gadoterate (a macrocyclic contrast agent). Materials and Methods Nine-week-old rats received five doses of 2.4 mmol gadolinium per kilogram of body weight over 5 weeks and were followed for 12 months with T1-weighted MRI (n = 140 rats, corresponding to seven time points, two contrast agents, and 10 rats per group). Animals were sacrificed at 1 week, 1 month, and 2, 3, 4, 5, and 12 months after the last injection. Brain and plasma were sampled to determine the total gadolinium concentration by using inductively coupled plasma mass spectrometry (ICP-MS). For the cerebellum, gadolinium speciation analysis was performed after mild extraction at four time points (1 month and 3, 5, and 12 months after the last injection) by using size exclusion chromatography and hydrophilic interaction liquid chromatography, both coupled to ICP-MS. Tissue gadolinium kinetics were fitted to estimate the area under the curves and tissue elimination half-lives over the 12-month injection-free period. Results T1 hyperintensity of the deep cerebellar nuclei was observed only in gadodiamide-treated rats and remained stable from the 1st month after the last injection (the ratio of the signal intensity of the deep cerebellar nuclei to the signal intensity of the brain stem at 1 year: 1.101 ± 0.023 vs 1.037 ± 0.022 before injection, P < .001). Seventy-five percent of the total gadolinium detected after the last injection of gadodiamide (3.25 nmol/g ± 0.30) was retained in the cerebellum at 1 year (2.45 nmol/g ± 0.35), with binding of soluble gadolinium to macromolecules. No T1 hyperintensity was observed with gadoterate, consistent with a rapid, time-dependent washout of the intact gadolinium chelate down to background levels (0.07 nmol/g ± 0.03). Conclusion After repeated administration of gadodiamide, a large portion of gadolinium was retained in the brain, with binding of soluble gadolinium to macromolecules. After repeated injection of gadoterate, only traces of the intact chelated gadolinium were observed with time-dependent clearance. Online supplemental material is available for this article.