Impact of Treatment With Chelating Agents Depends on the Stability of Administered GBCAs: A Comparative Study in Rats

Objective This study investigated the potential effect of the chelating agent calcium trisodium pentetate (Ca-DTPA) on the urinary excretion of gadolinium and the subsequent elimination of gadolinium (Gd) in the brain after a single intravenous administration of either a linear (gadodiamide) or a macrocyclic (gadobutrol) Gd-based contrast agent in rats. Materials and Methods Rats received either a single injection of gadodiamide or gadobutrol (1.8 mmol/kg, each) or saline (n = 18 per group). Seven weeks after the injection, 6 animals of each group were killed before the treatment period. From the remaining 12 animals, 6 received either 3 intravenous injections of Ca-DTPA (180 μmol/kg) or saline. Urine was collected daily for 3 days after each infusion. Gadolinium measurements by ICP-MS were performed in urine and tissue samples. Results In animals that initially received the linear gadodiamide, Ca-DTPA infusion increased the urinary excretion of Gd by a factor of 10 (cumulative amount of 114 ± 21 nmol Gd vs 10 ± 4 nmol Gd after saline infusion, P ≤ 0.0001). In contrast, animals that received the macrocyclic gadobutrol exhibited a higher spontaneous urinary excretion of Gd (33 ± 12 nmol after saline infusion) and Ca-DTPA had no impact (30 ± 11 nmol Gd, P = 0.68). The urinary excretion of Gd was associated with Gd brain content. Seven weeks after the initial Gd-based contrast agent administration, a total amount of 0.74 ± 0.053 nmol Gd was quantified in the brain after administration of gadodiamide. The Gd brain burden was partially reduced at the end of the treatment period in the animals that were repeatedly infused with Ca-DTPA (0.56 ± 0.13 nmol Gd, P = 0.009) but not with saline (0.66 ± 0.081 nmol, P = 0.32). In contrast, the total amount of macrocyclic gadobutrol measured in the brain was lower (0.11 ± 0.029 nmol Gd) and still spontaneously cleared during the 3-week saline infusion period (0.057 ± 0.019 nmol Gd (P = 0.003). Gadolinium quantified in the brain after infusions with Ca-DTPA did not differ from saline-infused animals (0.049 ± 0.014 nmol Gd). Conclusions Administration of the chelating agent Ca-DTPA 7 weeks after injection of linear gadodiamide induced relevant urinary Gd excretion. In parallel, the Gd amount in the brain tissue decreased. This indicates a dechelated pool among the chemical Gd forms present in the rat brain after linear gadodiamide administration that can be mobilized by chelation with Ca-DTPA. In contrast, Ca-DTPA did not mobilize Gd in animals that received macrocyclic gadobutrol, indicating that the Gd measured is intact gadobutrol. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Received for publication August 24, 2018; and accepted for publication, after revision, September 5, 2018. Conflicts of interest and sources of funding: none declared. Correspondence to: Janina Boyken, PhD, Institute of Physiology, Charité University Medicine, Berlin, Germany. E-mail: janina.boyken@charite.de. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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