Repeat and single dose administration of gadodiamide to rats to investigate concentration and location of gadolinium and the cell ultrastructure

Abstract

Gadolinium based contrast agents (GBCA) are used to image patients using magnetic resonance (MR) imaging. In recent years, there has been controversy around gadolinium retention after GBCA administration. We sought to evaluate the potential toxicity of gadolinium in the rat brain up to 1-year after repeated gadodiamide dosing and tissue retention kinetics after a single administration. Histopathological and ultrastructural transmission electron microscopy (TEM) analysis revealed no findings in rats administered a cumulative dose of 12 mmol/kg. TEM-energy dispersive X-ray spectroscopy (TEM-EDS) localization of gadolinium in the deep cerebellar nuclei showed ~ 100 nm electron-dense foci in the basal lamina of the vasculature. Laser ablation-ICP-MS (LA-ICP-MS) showed diffuse gadolinium throughout the brain but concentrated in perivascular foci of the DCN and globus pallidus with no observable tissue injury or ultrastructural changes. A single dose of gadodiamide (0.6 mmol/kg) resulted in rapid cerebrospinal fluid (CSF) and blood clearance. Twenty-weeks post administration gadolinium concentrations in brain regions was reduced by 16–72-fold and in the kidney (210-fold), testes (194-fold) skin (44-fold), liver (42-fold), femur (6-fold) and lung (64-fold). Our findings suggest that gadolinium does not lead to histopathological or ultrastructural changes in the brain and demonstrate in detail the kinetics of a human equivalent dose over time in a pre-clinical model.

Gadolinium: pharmacokinetics and toxicity in humans and laboratory animals following contrast agent administration

“…Fretellier et al (2019) also examined behavioural effects in juvenile or adult rats treated with 20 human equivalent doses of gadodiamide or gadoterate. There were no differences in the elevated plus maze, which corroborates existing literature which shows no hippocampal morphological changes or impairments in hippocampal neurogenesis, an area of the brain important in anxiolytic response and memory (Smith et al 2017;Alkhunizi et al 2020;Davies et al 2021). A T-maze is also a measure of hippocampal function and repeated dosing of gadodiamide and gadoterate revealed no significant changes compared to a control group (Alkhunizi et al 2020).…”

“…Excretion of intact molecules demonstrates no known metabolism of GBCAs and in rats the half-life of GBCAs is approximately 20 min (Oksendal and Hals 1993 ; Caravan et al 1999 ). Clearance from the blood follows first-order kinetics and a human equivalent dose in rats results in gadolinium below the limit of quantification (BLOQ) in the blood, 10 weeks post-dosing (Davies et al 2021 ). Following injection of the liver specific imaging agent gadoxetate, 50% of the injected dose is excreted via the liver in humans, compared with a higher proportion (70%) in rats, which qualitatively is a similar species difference to that observed with gadobenate (0.6–4% in humans, 25–55% in rats, dogs, rabbits and monkeys) (Schuhmann-Giampieri et al 1993 , 2014 ; Lorusso et al 1999 ; Eovist [package insert]).…”

“…The hyperintensity is concentrated in the dentate nucleus and globus pallidus of the deep cerebellar nuclei (DCN). And whilst this hyperintensity is correlated to gadolinium retention, it has not been associated with any histopathological changes in the brain (Lohrke et al 2017 ; Smith et al 2017 ; Davies et al 2021 ). Robert et al reported that the repeated administration of more than 30 times the human equivalent GBCA dose in rats resulted in significant T1 hyperintensity in the DCN of linear GBCA-treated animals, but not in rats treated with the macrocyclic class agent, gadoterate (Robert et al 2016 ).…”

“…We found that 1 h post-dosing gadolinium levels were unsurprisingly at their highest (subcortex; 2.67 ± 2.17 nmol/g, left hippocampus; 5.73 nmol/g, left cortex; 4.29 ± 2.30 nmol/g, left hemisphere rest-of-brain 4.27 ± 2.00 nmol/g, right hemisphere rest-of-brain; 4.23 ± 1.99 nmol/g). There was a significant reduction 1d post-dosing in all brain regions analysed, which remained at very low levels up to 20 weeks post-dosing and less than 0.00004% injected dose (id) in all brain areas, but did not fall below the range of quantification (Davies et al 2021 ). This demonstrates the rapid clearance from the brain, but with long-term retention of extremely small amounts of residual gadolinium.…”

“…Linear agents typically have slightly higher levels than macrocyclics, but brain retention of gadolinium has been demonstrated for all GBCAs, including macrocyclic agents (Bussi et al 2018b ). Transmission electron microscopy with energy-dispersive X-ray spectroscopy (TEM-EDS) has suggested the ultrastructural distribution of gadolinium is largely vascular and localised to the endothelium of capillaries on the luminal side of the BBB in rats (Davies et al 2021 ). The foci observed were amorphous, suggesting that these were not crystalline deposits of inorganic salts but in fact likely to be organic.…”