Speciation Analysis of Gadolinium in the Water-Insoluble Rat Brain Fraction After Administration of Gadolinium-Based Contrast Agents

Strzeminska, Izabela; Factor, Cécile; Robert, Philippe; Szpunar, Joanna; Corot, Claire; Łobiński, Ryszard

doi:10.1097/rli.0000000000000774

Cited by 9 publications

(11 citation statements)

References 34 publications

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“…Whilst this observation in rats has little relevance to the clinical situation, a different effect on the skin termed gadolinium associated plaques has been reported in an very small number of cases (3 patients) (Sieber et al 2008 ; Gathings et al 2015 ; Olayiwola et al 2019 ). The majority of animal studies have found no effect of GBCA administration on behavioural assessments and this is in agreement with the lack of neurological sequelae in patients (Bussi et al 2018b ; Fretellier et al 2019 ; Habermeyer et al 2020 ; Izabela Strzeminska et al 2021 ; Akai et al 2021 ). Whilst few animal studies have shown behavioural effects associated with supraclinical doses of GBCAs, there is no association with gadolinium concentration, and effects have been noted in both linear and macrocyclic GBCAs (Khairinisa et al 2018 ).…”

Section: Discussionsupporting

confidence: 69%

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

Davies¹,

Siebenhandl-Wolff²,

Tranquart³

et al. 2022

Arch Toxicol

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Gadolinium-based contrast agents (GBCAs) have transformed magnetic resonance imaging (MRI) by facilitating the use of contrast-enhanced MRI to allow vital clinical diagnosis in a plethora of disease that would otherwise remain undetected. Although over 500 million doses have been administered worldwide, scientific research has documented the retention of gadolinium in tissues, long after exposure, and the discovery of a GBCA-associated disease termed nephrogenic systemic fibrosis, found in patients with impaired renal function. An understanding of the pharmacokinetics in humans and animals alike are pivotal to the understanding of the distribution and excretion of gadolinium and GBCAs, and ultimately their potential retention. This has been well studied in humans and more so in animals, and recently there has been a particular focus on potential toxicities associated with multiple GBCA administration. The purpose of this review is to highlight what is currently known in the literature regarding the pharmacokinetics of gadolinium in humans and animals, and any toxicity associated with GBCA use.

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Section: Discussionsupporting

confidence: 69%

“…It is possible that GBCAs and also soluble gadolinium bound to macromolecules (e.g. ferritin) are sequestered in the choroid plexus (Strzeminska et al 2021 ). CSF allows distribution into the subarachnoid space, but a significant portion also drains to lymph nodes.…”

Section: Entry Of Gadolinium-based Contrast Agents Into the Human And...mentioning

confidence: 99%

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

Davies¹,

Siebenhandl-Wolff²,

Tranquart³

et al. 2022

Arch Toxicol

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“…The tissue homogenization disrupts cell membranes and exposes extracellular GBCAs and other Gd species to the intracellular components which can affect the equilibria present in vivo. Although the stability of GBCAs in the conditions of the sequential extraction procedure was previously verified, 26 the integrity of other, more fragile Gd species could be altered.…”

Section: Discussionmentioning

confidence: 97%

“…In the major brain structures such as cerebellum, cortex, or subcortical brain, it was previously shown that for L-GBCAs, at least 4 distinctive Gd species were present: small water-soluble molecules such as intact GBCAs, soluble macromolecules (with size estimations of superior to 66 kDa or of approximately 200-300 kDa), labile complexes of Gd 3+ with endogenous biomolecules, and in majority as insoluble species that were not further characterized. [23][24][25][26] So far, speciation studies using hyphenated techniques were limited to the analysis of larger brain structures and the tiny DCN (±9 mg) have never been analyzed separately from the cerebellum. Furthermore, Gd contained in the insoluble brain fraction was not analyzed in terms of speciation because of the lack of mild solubilization methods, rendering the studies incomplete in terms of mass balance of Gd, especially for the L-GBCAs.…”

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confidence: 99%

Comprehensive Speciation Analysis of Residual Gadolinium in Deep Cerebellar Nuclei in Rats Repeatedly Administered With Gadoterate Meglumine or Gadodiamide

et al. 2022

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Purpose: Several preclinical studies have reported the presence of gadolinium (Gd) in different chemical forms in the brain, depending on the class (macrocyclic versus linear) of Gd-based contrast agent (GBCA) administered. The aim of this study was to identify, with a special focus on insoluble species, the speciation of Gd retained in the deep cerebellar nuclei (DCN) of rats administered repeatedly with gadoterate or gadodiamide 4 months after the last injection. Methods: Three groups (N = 6/group) of healthy female Sprague-Dawley rats (SPF/OFA rats; Charles River, L'Arbresle, France) received a cumulated dose of 50 mmol/kg (4 daily intravenous administrations of 2.5 mmol/kg, for 5 weeks, corresponding to 80-fold the usual clinical dose if adjusted for man) of gadoterate meglumine (macrocyclic) or gadodiamide (linear) or isotonic saline for the control group (4 daily intravenous administrations of 5 mL/kg, for 5 weeks). The animals were sacrificed 4 months after the last injection. Deep cerebellar nuclei were dissected and stored at −80°C before sample preparation. To provide enough tissue for sample preparation and further analysis using multiple techniques, DCN from each group of 6 rats were pooled. Gadolinium species were extracted in 2 consecutive steps with water and urea solution. The total Gd concentrations were determined by inductively coupled plasma mass spectrometry (ICP-MS). Soluble Gd species were analyzed by size-exclusion chromatography coupled to ICP-MS. The insoluble Gd species were analyzed by single-particle (SP) ICP-MS, nanoscale secondary ion mass spectroscopy (NanoSIMS), and scanning transmission electron microscopy with energy-dispersive X-ray spectroscopy (STEM-EDX) for elemental detection. Results: The Gd concentrations in pooled DCN from animals treated with gadoterate or gadodiamide were 0.25 and 24.3 nmol/g, respectively. For gadoterate, the highest amount of Gd was found in the water-soluble fractions. It was present exclusively as low-molecular-weight compounds, most likely as the intact GBCA form. In the case of gadodiamide, the water-soluble fraction of DCN was composed of high-molecular-weight Gd species of approximately 440 kDa and contained only a tiny amount (less than 1%) of intact gadodiamide. Furthermore, the column recovery calculated for this fraction was incomplete, which suggested presence of labile complexes of dissociated Gd 3+ with endogenous molecules. The highest amount of Gd was detected in the insoluble residue, which was demonstrated, by SP-ICP-MS, to be a particulate form of Gd. Two imaging techniques (NanoSIMS and STEM-EDX) allowed further characterization of these insoluble Gd species. Amorphous, spheroid structures of approximately 100-200 nm of sea urchin-like shape were detected. Furthermore, Gd was consistently colocalized with calcium, oxygen, and phosphorous, strongly suggesting the presence of structures composed of mixed Gd/Ca phosphates. No or occasional colocalization with iron and sulfur was observed. Conclusion: A dedicated analytical workflow pr...

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“…The rst step in doing this is to develop suitable extraction methods that can efficiently isolate the compounds, without their degradation; this is no mean feat from a practical perspective. Working on brain tissues from rats 103 injected with either gadoterate The identity of the eluted species was investigated by using molecular size and retention time matching with Gd chelates and a ferritin standard. The LOQ was estimated using standard GBCA solutions to be 0.32 pmol mL À1 for all 3 GBCAs using a signal-to-noise >5 criterion.…”

Section: Gadoliniummentioning

confidence: 99%

Atomic Spectrometry Update: review of advances in elemental speciation

Clough

Harrington

Hill

et al. 2022

J. Anal. At. Spectrom.

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Speciation Analysis of Gadolinium in the Water-Insoluble Rat Brain Fraction After Administration of Gadolinium-Based Contrast Agents

Abstract: Supplemental digital content is available in the text.

Cited by 9 publications

References 34 publications

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

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

Comprehensive Speciation Analysis of Residual Gadolinium in Deep Cerebellar Nuclei in Rats Repeatedly Administered With Gadoterate Meglumine or Gadodiamide

Atomic Spectrometry Update: review of advances in elemental speciation

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