Differences in Molecular Structure Markedly Affect GBCA Elimination Behavior

Aime, Silvio

doi:10.1148/radiol.2019182748

Cited by 9 publications

(8 citation statements)

References 6 publications

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“…The limitations of our study include the assessment of the effect of the diabetic status on Gd retention in the animal model only, and further work needs to be performed to investigate the impact of the diabetic status on Gd retention and clearance in clinical patients. In addition, the results of this study only reflect findings for the three GBCAs tested, and the retention and clearance may be different with other GBCAs, such as gadoteridol (ProHance), which has previously been shown to clear more rapidly from normal rat brain and body tissues [5, 41, 42], possibly because of unique molecular properties [41, 43]. Further molecular investigations are needed to reveal the possible mechanisms by which decreased Gd retention occurs in diabetic brain tissues.…”

Section: Discussionmentioning

confidence: 92%

Gadolinium Retention and Clearance in the Diabetic Brain after Administrations of Gadodiamide, Gadopentetate Dimeglumine, and Gadoterate Meglumine in a Rat Model

Wang

Hua

Fan

et al. 2019

BioMed Research International

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Purpose. To evaluate gadolinium (Gd) retention and clearance in the brain of diabetic rats after administrations of gadodiamide, gadopentetate dimeglumine, and gadoterate meglumine. Materials and Methods. Both diabetic rats (n = 52) and normal rats (n = 52) intravenously received 20 injections of 0.6 mmol Gd/kg gadodiamide, gadopentetate dimeglumine, gadoterate meglumine, or saline. Both diabetic rats and normal rats were divided into 2 subgroups of 24 and 28 rats for the 7-day and 42-day evaluations (i.e., they were sacrificed at 7 days (n = 6 per group) and 42 days (n = 7 per group)), respectively, after the last injection. For the 7-day subgroup, 6 rats were euthanized for inductively coupled plasma mass spectrometry (ICP-MS) analysis. For the 42-day subgroup, 6 rats underwent T1-weighted magnetic resonance imaging (MRI) and ICP-MS, and 1 rat was analyzed by transmission electron microscopy (TEM). Results. The T1 enhancements in the deep cerebellar nuclei (DCNs) of diabetic rats were lower than those of normal rats in both linear Gd-based contrast agent (GBCA) groups (p < 0.05). The average Gd concentrations in the brains of diabetic rats were significantly lower than those of healthy rats in both the short-term groups and long-term groups (p < 0.05). The highest Gd retentions were in the olfactory bulb, DCN, and striatum with gadodiamide. Compared with the results obtained 7 days after the last injection, the residual Gd concentrations of the 42-day subgroups in the brains of diabetic rats showed no significant difference in both linear GBCA groups (p>0.05). Conclusions. Compared with normal rats, the diabetic status decreased the residual Gd concentrations in the brain after multiple administrations of gadodiamide, gadopentetate dimeglumine, and gadoterate meglumine. The clearable fraction of Gd in the brain was eliminated faster in diabetic rats than in normal rats.

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Section: Discussionmentioning

confidence: 92%

Gadolinium Retention and Clearance in the Diabetic Brain after Administrations of Gadodiamide, Gadopentetate Dimeglumine, and Gadoterate Meglumine in a Rat Model

Wang

Hua

Fan

et al. 2019

BioMed Research International

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“…Although assessment of potential long‐term safety issues was beyond the scope of this observational study, it is worth noting that all studies thus far performed in animals to evaluate Gd retention in brain and body tissues following GBCA exposure have shown that gadoteridol is retained to a lesser extent and cleared more rapidly than other GBCAs, including other macrocyclic GBCAs . Specifically, it appears that the unique molecular features of the gadoteridol molecule (low molecular weight and viscosity, neutrality, and high lipophilicity) are sufficient to markedly affect GBCA elimination behavior, leading to lower levels of retained Gd in the first weeks/months after exposure . Given that one rat year equates to roughly 30 human years, the reduced amount of Gd determined in rat brain and body tissues at weeks/months after gadoteridol administration would equate to several years in humans, if the findings in animals are considered indicative of the human situation.…”

Section: Discussionmentioning

confidence: 95%

Prospective Multicenter Study of the Safety of Gadoteridol in 6163 Patients

Cho

Lee

Chang

et al. 2019

Magnetic Resonance Imaging

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Background: The safety of gadolinium-based contrast agents is of fundamental importance. Purpose: To determine the frequency and severity of immediate-type adverse reactions to approved doses of gadoteridol in patients referred for routine gadoteridol-enhanced MRI in actual clinical practice settings. Study Type: Prospective, observational. Population: In all, 6163 subjects were enrolled (mean age: 56.7 AE 15.4 years; range: 6-93 years). Field Strength/Sequence: 1.5T and 3.0T. Assessment: Assessment was of immediate adverse reactions by the investigating radiologist using the MedDRA System Organ Class and preferred term. Statistical Tests: Summary statistics for continuous variables, descriptive statistics for demographic characteristics. Results: Overall, 19 adverse events occurred in 13 (0.21%) patients, of which 15 in 10 (0.16%) patients were considered related to gadoteridol administration. These events were evenly distributed between male and female subjects and all occurred in adults. Twelve of the 15 related events in eight (0.13%) patients were considered mild in intensity (rapidly selfresolving), while the remaining three events in two patients (0.03%) were considered moderate in intensity. None were of severe intensity and no serious adverse events occurred. Data Conclusion: The rate of immediate-type adverse events following exposure to approved doses of gadoteridol is extremely low, and mostly limited to transient and self-resolving symptoms. Level of Evidence: 2 Technical Efficacy Stage: 5This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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“…Although the retained Gd levels were similar for the three macrocyclic GBCAs at 26 and 52 weeks after the last administration [13], these findings suggest that ProHance is cleared more rapidly than Dotarem or Gadovist, possibly reflecting more efficient migration of the gadoteridol molecule towards the venous and lymphatic vessels in the interstitial space. In this regard, it appears molecular migration is promoted not only by convection, which is unaffected by small differences in otherwise similar molecules, but also by diffusion, which is highly dependent on the intrinsic molecular properties of the GBCAs and their capacity for interaction with the complex surrounding matrix [41].…”

Section: Tissue Gd Concentrationsmentioning

confidence: 99%

Macrocyclic MR contrast agents: evaluation of multiple-organ gadolinium retention in healthy rats

et al. 2020

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Objectives: The purpose of this study was to compare Gd levels in rat tissues after cumulative exposure to four commercially available macrocyclic gadolinium-based contrast agents (GBCAs). Methods: Sixty-five male Sprague-Dawley rats were randomized to four exposure groups (n = 15 per group) and one control group (n = 5). Animals in each exposure group received 20 GBCA administrations (four per week of ProHance®, Dotarem®, Clariscan™, or Gadovist® for 5 consecutive weeks) at a dose of 0.6 mmol/kg bodyweight. After 28-days' recovery, animals were sacrificed and tissues harvested for Gd determination by inductively coupled plasma-mass spectroscopy (ICP-MS). Histologic assessment of the kidney tissue was performed for all animals.

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Differences in Molecular Structure Markedly Affect GBCA Elimination Behavior

Cited by 9 publications

References 6 publications

Gadolinium Retention and Clearance in the Diabetic Brain after Administrations of Gadodiamide, Gadopentetate Dimeglumine, and Gadoterate Meglumine in a Rat Model

Gadolinium Retention and Clearance in the Diabetic Brain after Administrations of Gadodiamide, Gadopentetate Dimeglumine, and Gadoterate Meglumine in a Rat Model

Prospective Multicenter Study of the Safety of Gadoteridol in 6163 Patients

Macrocyclic MR contrast agents: evaluation of multiple-organ gadolinium retention in healthy rats

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