Fretellier, Nathalie and Salhi, Mariem and Schroeder, Josef and Siegmund, Heiko and Chevalier, Thibaut and Bruneval, Patrick and Jestin-Mayer, Gaelle and Delaloge, Francette and Factor, Cecile and Mayer, Jean-Francois and Fabicki, Jean-Michel and Robic, Caroline and Bonnemain, Bruno and Idee, Jean-Marc and Corot, Claire (2015) Distribution profile of gadolinium in gadolinium chelate-treated renally-impaired rats: Role of pharmaceutical formulation. EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES, 72. pp. 46-56. ISSN 0928-0987, 1879-0720
Full text not available from this repository. (Request a copy)Abstract
While not acutely toxic, chronic hepatic effect of certain gadolinium chelates (GC), used as contrast agent for magnetic resonance imaging, might represent a risk in renally-impaired patients due to free gadolinium accumulation in the liver. To answer this question, this study investigated the consequences of the presence of small amounts of either a soluble gadolinium salt ("free" Gd) or low-stability chelating impurity in the pharmaceutical solution of gadoteric acid, a macrocyclic GC with high thermodynamic and kinetic stabilities, were investigated in renally-impaired rats. Renal failure was induced by adding 0.75% adenine in the diet for three weeks. The pharmaceutical and commercial solution of gadoteric acid was administered (5 daily intravenous injections of 2.5 mmol Gd/kg) either alone or after being spiked with either "free" gadolinium (i.e., 0.04% w/v) or low-stability impurity (i.e., 0.06 w/v). Another GC, gadodiamide (low thermodynamic and kinetic stabilities) was given as its commercial solution at a similar dose. Non-chelated gadolinium was tested at two doses (0.005 and 0.01 mmol Gd/kg) as acetate salt. Gadodiamide induced systemic toxicity (mortality, severe epidermal and dermal lesions) and substantial tissue Gd retention. The addition of very low amounts of "free", non-chelated gadolinium or low thermodynamic stability impurity to the pharmaceutical solution of the thermodynamically stable GC gadoteric acid resulted in substantial capture of metal by the liver, similar to what was observed in "free" gadolinium salt-treated rats. Relaxometry studies strongly suggested the presence of free and soluble gadolinium in the liver. Electron microscopy examinations revealed the presence of free and insoluble gadolinium deposits in hepatocytes and Kupffer cells of rats treated with gadoteric acid solution spiked with low-stability impurity, free gadolinium and gadodiamide, but not in rats treated with the pharmaceutical solution of gadoteric acid. The presence of impurities in the GC pharmaceutical solution may have long-term biological consequences. (C) 2015 Elsevier B.V. All rights reserved.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | NEPHROGENIC SYSTEMIC FIBROSIS; IMAGING CONTRAST AGENTS; IN-VIVO; LIVER METASTASES; TUMOR-GROWTH; KUPFFER; STABILITY; MODEL; MICE; SKIN; Gadolinium chelates; Gadolinium; Contrast agents; Pharmaceutical solution; Magnetic resonance imaging; Drug impurities |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Pathologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 18 Jul 2019 07:37 |
| Last Modified: | 18 Jul 2019 07:37 |
| URI: | https://pred.uni-regensburg.de/id/eprint/5481 |
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