Gadolinium Retention in the Rat Brain: Assessment of the Amounts of Insoluble Gadolinium-containing Species and Intact Gadolinium Complexes after Repeated Administration of Gadolinium-based Contrast Agents

Abstract

Purpose To evaluate the speciation of gadolinium-containing species after multiple administrations of the gadolinium-based contrast agents (GBCAs) gadodiamide and gadoteridol and to quantify the amount of intact gadolinium complexes and insoluble gadolinium-containing species. Materials and Methods A total dose of 13.2 mmol per kilogram of body weight of each GBCA was administered in healthy Wistar rats over a period of 8 weeks. Three days after the final administration, rats were sacrificed, and the brains were excised and divided into three portions. Each portion of brain homogenate was divided into two parts, one for determination of the total gadolinium concentration with inductively coupled plasma mass spectrometry and one for determination of the amount of intact GBCA and gadolinium-containing insoluble species. Relaxometric measurements of gadodiamide and gadolinium trichloride in the presence of polysialic acid were also performed. Results The mean total gadolinium concentrations for gadodiamide and gadoteridol, respectively, were 0.317 μg/g ± 0.060 (standard deviation) and 0.048 μg/g ± 0.004 in the cortex, 0.418 μg/g ± 0.078 and 0.051 μg/g ± 0.009 in the subcortical brain, and 0.781 μg/g ± 0.079 and 0.061 μg/g ± 0.012 in the cerebellum. Gadoteridol comprised 100% of the gadolinium species found in rats treated with gadoteridol. In rats treated with gadodiamide, the largest part of gadolinium retained in brain tissue was insoluble species. In the cerebellum, the amount of intact gadodiamide accounts for 18.2% ± 10.6 of the total gadolinium found therein. The mass balance found for gadolinium implies the occurrence of other soluble gadolinium-containing species (approximately 30%). The relaxivity of the gadolinium polysialic acid species formed in vitro was 97.8 mM/sec at 1.5 T and 298 K. Conclusion Gadoteridol was far less retained, and the entire detected gadolinium was intact soluble GBCA, while gadodiamide yielded both soluble and insoluble gadolinium-containing species, with insoluble species dominating. RSNA, 2017 Online supplemental material is available for this article.

Integration of gadolinium in nanostructure for contrast enhanced‐magnetic resonance imaging

“…However, mechanism and chemical form of Gd retention in the body still need to be defined. More recently, it has been shown that the repeated use of GBCA could lead to the Gd deposition in various organs including brain, kidney, bones, and so forth (Do et al, ; Gianolio et al, ; Kanda et al, ; Reeder & Gulani, ; Runge, ). Because of these growing concerns and potential toxicity of GBCAs, the European Medicines Agency (EMA) has suspended or restricted the use of linear GBCAs in Europe.…”

Chemical Insights into the Issues of Gd Retention in the Brain and Other Tissues Upon the Administration of Gd‐Containing MRI Contrast Agents

“…To tackle this task, we evaluated the speciation of gadolinium containing species in rats' brains after multiple administrations of Gd(DTPA‐BMA) and Gd(HP‐DO3A) . This work allowed us to quantify the amount of intact gadolinium complexes and to evaluate the occurrence of insoluble gadolinium containing species.…”

“…Summary of the experimental protocol used to assess total gadolinium, the amount of intact GBCA, and Gd in insoluble forms. Adapted from ref . Copyright 2017 Radiological Society of North America.…”

The Effects of Gadolinium-Based Contrast Agents on the Cerebellum: from Basic Research to Neurological Practice and from Pregnancy to Adulthood

“…Studies using animal models have shown that GBCAs may be deposited in the brain after repeated injections [1][2][3]. Tissue depositions of linear GBCAs are much higher than those of macrocyclic GBCA.…”

“…Furthermore, the Gd deposition has also been observed in the cerebellar cortex [3,7]. Gd compounds deposited in the cerebellum consist of both soluble and insoluble forms [1,2]. Soluble form may be intact GBCA, whereas insoluble form may be Gd bound with organic or inorganic anions, although the exact chemical nature of insoluble form has not yet fully clarified.…”