title: Linear Gadolinium-Based Contrast Agents Are Associated With Brain Gadolinium Retention in Healthy Rats.
abstract: OBJECTIVE
  The aim of this study was to evaluate Gd retention in the deep cerebellar nuclei (DCN) of linear gadolinium-based contrast agents (GBCAs) compared with a macrocyclic contrast agent.
  
  
  METHODS
  The brain tissue retention of Gd of 3 linear GBCAs (gadobenate dimeglumine, gadopentetate dimeglumine, and gadodiamide) and a macrocyclic GBCA (gadoterate meglumine) was compared in healthy rats (n = 8 per group) that received 20 intravenous injections of 0.6 mmol Gd/kg (4 injections per week for 5 weeks). An additional control group with saline was included. T1-weighted magnetic resonance imaging was performed before injection and once a week during the 5 weeks of injections and for another 4 additional weeks after contrast period. Total gadolinium concentration was measured with inductively coupled plasma mass spectrometry. Blinded qualitative and quantitative evaluations of the T1 signal intensity in DCN were performed, as well as a statistical analysis on quantitative data.
  
  
  RESULTS
  At completion of the injection period, all the linear contrast agents (gadobenate dimeglumine, gadopentetate dimeglumine, and gadodiamide) induced a significant increase in signal intensity in DCN, unlike the macrocyclic GBCA (gadoterate meglumine) or saline. The T1 hypersignal enhancement kinetic was fast for gadodiamide. Total Gd concentrations for the 3 linear GBCAs groups at week 10 were significantly higher in the cerebellum (1.21 ± 0.48, 1.67 ± 0.17, and 3.75 ± 0.18 nmol/g for gadobenate dimeglumine, gadopentetate dimeglumine, and gadodiamide, respectively) than with the gadoterate meglumine (0.27 ± 0.16 nmol/g, P < 0.05) and saline (0.09 ± 0.12 nmol/g, P < 0.05). No significant difference was observed between the macrocyclic agent and saline.
  
  
  CONCLUSIONS
  Repeated administrations of the linear GBCAs gadodiamide, gadobenate dimeglumine, and gadopentetate dimeglumine to healthy rats were associated with progressive and significant T1 signal hyperintensity in the DCN, along with Gd deposition in the cerebellum. This is in contrast with the macrocyclic GBCA gadoterate meglumine for which no effect was observed.
authors.affiliation: From the *Guerbet Research and Innovation Department, Aulnay-sous-Bois; †INSERM, U836; ‡Université Grenoble Alpes, Grenoble Institute of Neurosciences, Grenoble; §Institut du Cerveau et de la Moelle Epinière, Centre de Neuroimagerie de Recherche; ∥Sorbonne Universités, Université Pierre et Marie Curie-Paris 6, INSERM UMR-S1127, CNRS 7225; and ¶Service de Neuroradiologie, Hôpital de la Pitié-Salpêtrière, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Robert
authors.forename: Xavier
authors.initials: X
authors.lastname: Violas
authors.forename: Sylvie
authors.initials: S
authors.lastname: Grand
authors.forename: Stéphane
authors.initials: S
authors.lastname: Lehericy
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Idée
authors.forename: Sébastien
authors.initials: S
authors.lastname: Ballet
authors.forename: Claire
authors.initials: C
authors.lastname: Corot
mesh_terms: D000818:Animals; D002529:Cerebellar Nuclei / Q000378:metabolism*; D003287:Contrast Media / Q000493:pharmacokinetics*; D005260:Female; D019786:Gadolinium DTPA / Q000493:pharmacokinetics*; D008279:Magnetic Resonance Imaging / Q000379:methods; D008536:Meglumine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D008657:Metabolic Clearance Rate; D009942:Organometallic Compounds / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D014018:Tissue Distribution
chemical_list: D003287:Contrast Media; D009942:Organometallic Compounds; C064572:gadobenic acid; D008536:Meglumine; C064925:gadodiamide; D019786:Gadolinium DTPA; C072417:gadoterate meglumine