Comparison of gadolinium concentrations within multiple rat organs after intravenous administration of linear versus macrocyclic gadolinium chelates

Purpose: To compare gadolinium tissue concentrations of multiple linear and macrocyclic chelates in a rat model to better understand the scope and extent of tissue deposition following multiple intravenous doses of gadolinium-based contrast agent (GBCA). Materials and Methods: In this Institutional Animal Care and Use Committee-approved study, healthy rats received 20 intravenous injections of 2.5 mmol gadolinium per kilogram (gadolinium-exposed group) or saline (control group) over a 26-day period. Unenhanced T1 signal intensities of the dentate nucleus were measured from magnetic resonance (MR) images obtained prior to GBCA injection and 3 days after final injection. Rat brain and renal, hepatic, and splenic tissues were harvested 7 days after final injection and subjected to inductively coupled plasma mass spectrometry and transmission electron microscopy for quantification and characterization of gadolinium deposits. Results: Gadolinium deposition in brain tissue significantly varied with GBCA type (F = 31.2; P < .0001), with median concentrations of 0 mg gadolinium per gram of tissue (95% confidence interval [CI]: 0, 0.2) in gadoteridol-injected rats, 1.6 mg gadolinium per gram of tissue (95% CI: 0.9, 4.7) in gadobutrol-injected rats, 4.7 mg gadolinium per gram of tissue (95% CI: 3.5, 6.1) in gadobenate dimeglumine-injected rats, and 6.9 mg gadolinium per gram of tissue (95% CI: 6.2, 7.0) in gadodiamide-injected rats; a significant positive dose-signal intensity correlation was identified (r = 0.93; P < .0001). No detectable neural tissue deposition or MR imaging signal was observed in control rats (n = 6). Similar relative differences in gadolinium deposition were observed in renal, hepatic, and splenic tissues at much higher tissue concentrations (P < .0001). Gadolinium deposits were visualized directly in the endothelial capillary walls and neural interstitium in GBCA-injected rats, but not in control rats. Conclusion: Tissue deposition of gadolinium was two- to fourfold higher following administration of the linear agents gadodiamide and gadobenate dimeglumine compared with the macrocyclic agents gadobutrol and gadoteridol. These findings suggest that organ tissue deposition is reduced but not eliminated following administration of macrocyclic GBCA chelates in lieu of linear chelates.