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.