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Gadolinium-based Contrast Agent Biodistribution and Speciation in Rats
Mariane Le Fur1, Brianna F Moon1, Iris Y Zhou1
1From the Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology (M.L.F., B.F.M., I.Y.Z., S.Z., A.B., N.J.R., I.A., P.P., D.I.G., P.C.), Department of Urology (A.S.F.), and Department of Pathology (I.A.R., I.D.A.L.H., L.P.H.), Massachusetts General Hospital and Harvard Medical School, 149 13th St, Charlestown, MA 02129; Institute for Innovation in Imaging, Massachusetts General Hospital, Charlestown, Mass (M.L.F., B.F.M., I.Y.Z., S.Z., A.B., N.J.R., I.A., P.P., P.C.); Harvard-MIT Health Sciences and Technology, Cambridge, Mass (D.I.G.); Bioengineering Department, Universidad Carlos III de Madrid, Madrid, Spain (D.I.G.); Department of Chemistry and Biochemistry, University of Arizona, Tucson, Ariz (A.V.A.); and Trace Element Analysis Laboratory, Dartmouth College, Hanover, NH (B.P.J.).
Abstract:
Background Gadolinium retention has been observed in organs of patients with normal renal function; however, the biodistribution and speciation of residual gadolinium is not well understood. Purpose To compare the pharmacokinetics, distribution, and speciation of four gadolinium-based contrast agents (GBCAs) in healthy rats using MRI, mass spectrometry, elemental imaging, and electron paramagnetic resonance (EPR) spectroscopy. Materials and Methods In this prospective animal study performed between November 2021 and September 2022, 32 rats received a dose of gadoterate, gadoteridol, gadobutrol, or gadobenate (2.0 mmol/kg) for 10 consecutive days. GBCA-naive rats were used as controls. Three-dimensional T1-weighted ultrashort echo time images and R2* maps of the kidneys were acquired at 3, 17, 34, and 52 days after injection. At 17 and 52 days after injection, gadolinium concentrations in 23 organ, tissue, and fluid specimens were measured with mass spectrometry; gadolinium distribution in the kidneys was evaluated using elemental imaging; and gadolinium speciation in the kidney cortex was assessed using EPR spectroscopy. Data were assessed with analysis of variance, Kruskal-Wallis test, analysis of response profiles, and Pearson correlation analysis. Results For all GBCAs, the kidney cortex exhibited higher gadolinium retention at 17 days after injection than all other specimens tested (mean range, 350-1720 nmol/g vs 0.40-401 nmol/g; P value range, .001-.70), with gadoteridol showing the lowest level of retention. Renal cortex R2* values correlated with gadolinium concentrations measured ex vivo (r = 0.95; P < .001), whereas no associations were found between T1-weighted signal intensity and ex vivo gadolinium concentration (r = 0.38; P = .10). EPR spectroscopy analysis of rat kidney cortex samples showed that all GBCAs were primarily intact at 52 days after injection. Conclusion Compared with other macrocyclic GBCAs, gadoteridol administration led to the lowest level of retention. The highest concentration of gadolinium was retained in the kidney cortex, but T1-weighted MRI was not sensitive for detecting residual gadolinium in this tissue. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Tweedle in this issue.
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