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Clinical, Biological, and Skin Histopathologic Effects of Ionic Macrocyclic and Nonionic Linear Gadolinium Chelates in a Rat Model of Nephrogenic Systemic Fibrosis

Fretellier, Nathalie MS*; Idée, Jean-Marc PharmD*; Guerret, Sylviane PhD†; Hollenbeck, Claire BS*; Hartmann, Daniel PharmD‡; González, Walter PhD*; Robic, Caroline PhD*; Port, Marc PhD*; Corot, Claire PharmD*

doi: 10.1097/RLI.0b013e3181f54044
Original Article

Objective: The purpose of this study was to compare the clinical, pathologic, and biochemical effects of repeated administrations of ionic macrocyclic or nonionic linear gadolinium chelates (GC) in rats with impaired renal function.

Material and Methods: Rats submitted to subtotal nephrectomy were allocated to single injections of 2.5 mmol/kg of gadodiamide (nonionic linear chelate), nonformulated gadodiamide (ie, without the free ligand caldiamide), gadoterate (ionic macrocyclic chelate), or saline for 5 consecutive days. Blinded semi-quantitative histopathologic and immunohistochemical examinations of the skin were performed, as well as clinical, hematological, and biochemical follow-up. Rats were killed at day 11. Long-term (up to day 32) follow-up of rats was also performed in an auxiliary study.

Results: Epidermal lesions (ulcerations and scabs) were found in 4 of the 10 rats treated with nonformulated gadodiamide. Two rats survived the study period. Inflammatory signs were observed in this group. No clinical, hematological, or biochemical signs were observed in the saline and gadoterate- or gadodiamide-treated groups. Plasma fibroblast growth factor-23 levels were significantly higher in the gadodiamide group than in the gadoterate group (day 11). Decreased plasma transferrin-bound iron levels were measured in the nonformulated gadodiamide group. Histologic lesions were in the range: nonformulated gadodiamide (superficial epidermal lesions, inflammation, necrosis, and increased cellularity in papillary dermis) > gadodiamide (small superficial epidermal lesions and signs of degradation of collagen fibers in the dermis) > gadoterate (very few pathologic lesions, similar to control rats).

Conclusions: Repeated administration of the nonionic linear GC gadodiamide to renally impaired rats is associated with more severe histologic lesions and higher FGF-23 plasma levels than the macrocyclic GC gadoterate.

From the *Guerbet, Research Division, Aulnay-Sous-Bois, France; †Novotec, Lyon, France; and ‡School of Pharmacy, USPS 2007.03.135, University Claude Bernard Lyon I, Lyon, France.

Received May 20, 2010; accepted for publication, after revision, July 10, 2010.

Reprints: Jean-Marc Idée, PharmD, MS, Research Division, BP 57400, 95943 Roissy Charles de Gaulle Cedex, France. E-mail: jean-marc.idee@guerbet-group.com.

© 2011 Lippincott Williams & Wilkins, Inc.