Impact of chelation timing on gadolinium deposition in rats after contrast administration.

OBJECTIVE: To determine if gadolinium (Gd) can be rechelated once released from Gd-based contrast agents (GBCAs) and deposited in vivo. Despite extensive research comparing GBCAs and GBCA formulations as well as the ongoing debate about their risks of deposition and the role of Gd release, it remains unknown if retained Gd can be eliminated by administering chelating agents. MATERIALS AND METHODS: Rats were injected intravenously with 10 doses of 1 mmol/kg gadodiamide and treated with intravenous Zn-DTPA (30 µmol/kg) concomitantly or 1, 4 or 8 h after GBCA administration (N = 3 rats per group). After euthanization, tissues were harvested three days after the last dose of gadodiamide and tissue Gd concentrations were assessed by ICP-MS. Additionally, a simulation of a single 0.1 mmol/kg gadopentetate dose with 30 µmol/kg DTPA given either concomitantly or within the first 24 h after GBCA was run; simulated tissue Gd concentrations were compared with those observed in rats to determine if simulated trends were accurate. RESULTS: Concomitant DTPA did not produce a significant reduction in Gd concentration in any organ for rats. There was a time-dependent trend in liver Gd reduction. The 1 h timepoint was associated with a non-significant increase in kidney, brain and femur Gd relative to untreated controls. There were no significant deviations from the model-predicted Gd changes. DISCUSSION: Both the simulation and rat study did not identify major benefits for chelation at the doses given, despite the simulation assuming all Gd deposited in tissues is unchelated. The potential redistribution in the rat study provide a compelling result that may impact the clinical relevance of further work investigating rechelation of Gd. Future work should further describe the three-dimensional dose-time-response relationship for preventing Gd deposition, and how that relates to long-term Gd toxicities.

Solid-State Characterization of Three Polymorphs of an Orally Available Analog of Diethylenetriaminepentaacetic Acid.

The present work investigated the physical and thermal characteristics of three polymorphic forms (namely, PF1, PF2, and PF3) of a diethyl ester analog of diethylenetriaminepentaacetic acid (C2E2) produced under varying conditions. The identity of each form of C2E2 was confirmed by 1H-NMR, 13C-NMR, and mass spectroscopy. The different polymorphic forms exhibited solubilities ranging from 40 to 150 mg/mL. Powder X-ray diffraction (PXRD) and electron microscopy confirmed that all three forms were crystalline, two of which being scaly, and the third being well-formed. Infrared and Raman spectroscopy revealed differences in the C = O bonding region while differential scanning calorimetry (DSC) and thermal gravimetric analysis (TGA) showed widely different melting points with only one thermal event for each compound. The comparison of the melting points and heats of fusion show that the PF1 is monotropically related to both PF2 and PF3, while PF2 and PF3 are enantropically related. Our finding indicates that PF3 is the thermodynamically stable polymorph and will be used for in vitro and in vivo experiments.

Gadolinium deposition in the brain: Lessons learned from other metals known to cross the blood-brain barrier.

The recent discovery of gadolinium (Gd) deposition in the brains of patients receiving Gd-based contrast agents (GBCAs) raises several important questions including by what mechanism Gd or GBCAs pass through the blood-brain barrier. Decades of research focused on the safety and stability of GBCAs have not identified any mechanism of uptake. Here we review findings of Gd deposition from human and animal data, and how distribution mechanisms elucidated for endogenous and toxic metals may explain entrance of Gd into the central nervous system. Three general uptake mechanisms are considered along with examples of metals known to enter the central nervous system by these routes: (1) carrier-mediated, (2) transporter-mediated and (3) passive. The potential for chelation therapy to reduce deposition is also discussed. The work reported for other metals provides guidance for how the mechanism of Gd deposition in the brain can be determined which is essential information for rational prevention or treatment.