Clearance of Gadolinium from the Brain with No Pathologic Effect after Repeated Administration of Gadodiamide in Healthy Rats: An Analytical and Histologic Study

Abstract

Purpose To measure the levels of gadolinium present in the rat brain 1 and 20 weeks after dosing with contrast agent and to determine if there are any histopathologic sequelae. Materials and Methods The study was approved by the GE Global Research Center Institutional Animal Care and Use Committee. Absolute gadolinium levels were quantified in the blood and brains of rats 1 week after dosing and 20 weeks after dosing with up to 20 repeat doses of gadodiamide (cumulative dose, 12 mmol per kilogram of body weight) by using inductively coupled plasma-mass spectrometry. Treatment groups (n = 6 rats per group) included low-dosage and high-dosage gadodiamide and osmolality-matched saline controls. Brain sections were submitted (blinded) for standard toxicology assessment per Registry of Industrial Toxicology Animal data guidelines. Analysis of variance and Mann-Whitney U tests with post hoc correction were used to assess differences in absolute gadolinium levels and percentage of injected dose, respectively. Results Dose-dependent low levels of gadolinium were detected in the brain, a mean ± standard deviation of 2.49 nmol per gram of brain tissue ± 0.30 or 0.00019% of the injected dose 1 week after dosing. This diminished by approximately 50% (to 1.38 nmol per gram of brain tissue ± 0.10 or 0.00011% of the injected dose) 20 weeks after dosing. As a percentage of injected dose, the levels of gadolinium measured were comparable between different doses, indicating that mechanisms of uptake and elimination were not saturated at the tested doses. There were no histopathologic findings associated with the levels of gadolinium measured. Conclusion Low levels of gadolinium are present in the brain after repeat dosing with gadodiamide, which is partially cleared over 20 weeks with no detectable neurotoxicity.

Critical Questions Regarding Gadolinium Deposition in the Brain and Body After Injections of the Gadolinium-Based Contrast Agents, Safety, and Clinical Recommendations in Consideration of the EMA's Pharmacovigilance and Risk Assessment Committee Recommendation for Suspension of the Marketing Authorizations for 4 Linear Agents

“…35 Evaluation of low-and high-dose groups indicated that the uptake mechanisms were not saturated (greater deposition occurred at higher doses). Quantitative measures revealed partial clearance (a decrease by about half ) in comparison with the 1-and 20-week postdose groups.…”

Differences in gadolinium retention after repeated injections of macrocyclic MR contrast agents to rats

“…[11][12][13] Unfortunately, given the unfeasibility of acquiring tissue samples from live human patients, most studies performed to evaluate Gd retention in the brain have utilized animal, typically rat, models and have focused primarily on quantifying T 1 signal increases and/or Gd retention after exposure to macrocyclic GBCAs versus linear GBCAs. [14][15][16][17][18][19][20][21][22] To date, no studies have compared the three available macrocyclic agents: gadoterate (Dotarem; Guerbet, Roissy, France), gadobutrol (Gadovist; Bayer Pharma, Berlin, Germany), and gadoteridol (ProHance; Bracco Imaging, Milan, Italy) in terms of their susceptibility to Gd retention. Our purpose was to determine whether these three macrocyclic GBCAs differ in terms of their propensity to deposit Gd in selected rat tissues.…”

Analysis of retention of gadolinium by brain, bone, and blood following linear gadolinium‐based contrast agent administration in rats with experimental sepsis

“…This has been challenged by observations that unenhanced T 1 signal intensity increases with normal myelination as children mature, and by underlying pathological processes, which may complicate the interpretation of increasing unenhanced T 1 signal intensity as indicative of Gd deposition in patients who undergo multiple MRI examinations over time . No adverse clinical or pathological consequences of Gd deposition in the brain have thus far been confirmed . However, precautionary recommendations have been made in the use of linear GBCA by professional organizations and the Food and Drug Administration .…”

“…This has led to a new concern that linear GBCA, which undergoes dechelation, results in Gd deposition in many tissues, including the brain and bone. The significance of this concern has been challenged by the broad radiology community and lack of current clinical evidence of deleterious effects . However, linear GBCA have been largely withdrawn in Europe in favor of macrocyclic agents, which do not undergo dechelation .…”

“…The significance of this concern has been challenged by the broad radiology community and lack of current clinical evidence of deleterious effects. [12][13][14][15] However, linear GBCA have been largely withdrawn in Europe in favor of macrocyclic agents, which do not undergo dechelation. 16 The Food and Drug Administration has issued warnings regarding the use of GBCA in potentially vulnerable populations, such as children and those with blood-brain barrier (BBB) disruption.…”