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ORIGINAL RESEARCH article
Front. Toxicol.
Sec. Clinical Toxicology
Volume 6 - 2024 |
doi: 10.3389/ftox.2024.1403031
This article is part of the Research Topic Magnetic Resonance Imaging Contrast Agents: The Safety of Gadolinium View all 3 articles
The Effect of Iron Status on Gadolinium Deposition in the Rat Brain: Mechanistic Implications
Provisionally accepted- 1 Pharmacometrics, Pfizer, New York, United States
- 2 University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
Sites associated with gadolinium (Gd) deposition in the brain (e.g., the globus pallidus) are known to contain high concentrations of ferric iron. There is considerable debate over the mechanism of Gd deposition in the brain. The role of iron transport mechanisms in Gd deposition has not been determined. Thus, we seek to identify if Gd deposition can be controlled by modifying iron exposure. Female Sprague-Dawley rats were given diets with controlled iron levels at 2-6 ppm, 6 ppt (20 g/kg Fe carbonyl) or 48 ppm for three weeks to induce iron deficiency, overload or normalcy. They were kept on those diets while receiving a cumulative 10 mmol/kg dose of gadodiamide intravenously over two weeks, then left to washout gadodiamide for 3 days or 3 weeks before tissues were harvested. Gd concentrations in tissues were analyzed by ICP-MS. There were no significant effect of dietary iron and total Gd concentrations in the organs, but there was a significant effect of iron status on Gd distribution in the brain. For the 3-week washout cohort, there was a non-significant trend of increasing total brain deposition and decreasing dietary iron, and about 4-fold more Gd in the olfactory bulbs of the low iron group compared to the other groups. Significant brain accumulation was observed in the low iron group total brain Gd in the 3-week washout group relative to the 3-day washout group and no accumulation was observed in other tissues. There was a strong negative correlation between femur Gd concentrations and concentrations in other organs when stratifying by dietary iron. Gd brain deposition from linear Gd-based contrast agents (GBCAs) are dependent upon iron status, likely through variable transferrin saturation. This iron dependence appears to be associated with redistribution of peripheral deposited Gd (e.g., in the bone) into the brain.
Keywords: Gadolinium, Toxicokinetics (TK), iron deficiency, Iron overload (IO), MRI
Received: 18 Mar 2024; Accepted: 17 Jul 2024.
Copyright: © 2024 Prybylski and Jay. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
John P. Prybylski, Pharmacometrics, Pfizer, New York, United States
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Michael Jay
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