Total gadolinium tissue deposition and skin structural findings following the administration of structurally different gadolinium chelates in healthy and ovariectomized female rats.

OBJECTIVE: To assess the retention of gadolinium (Gd) in skin, liver, and bone following gadodiamide or gadoteric acid administration. METHODS: Gd was measured in skin, liver and femur bone in female rats 10 weeks after administration of 17.5 mmol Gd/kg over 5 days of Gd agents. Rat skin microscopy, energy filtering transmission electron microscopy and elemental analysis were performed, and repeated after receiving the same dosage of gadodiamide in rats with osteoporosis induced with bilateral ovariectomy (OVX). The OVX was performed 60 days after the last injection of gadodiamide and animals sacrificed 3 weeks later. RESULTS: Gd concentration was 180-fold higher in the skin, 25-fold higher in the femur, and 30-fold higher in the liver in rats received gadodiamide than rats received gadoteric acid. The retention of Gd in the skin with gadodiamide was associated with an increase in dermal cellularity, and Gd encrustation of collagen fibers and deposition inside the fibroblasts and other cells. No differences in Gd concentration in liver, skin, and femur were observed between rats receiving gadodiamide with or without OVX. CONCLUSIONS: Gd tissue retention with gadodiamide was higher than gadoteric acid. Tissues Gd deposition did not alter following gadodiamide administration to ovariectomized rats.

Distribution profile of gadolinium in gadolinium chelate-treated renally-impaired rats: role of pharmaceutical formulation.

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.

Safety profiles of gadolinium chelates in juvenile rats differ according to the risk of dissociation.

This study was designed to compare the safety of two gadolinium chelates (GCs), used as contrast agents for magnetic resonance imaging, in juvenile rats. Juvenile rats received five intravenous administrations (between postnatal day [PND] 4 and 18) of gadoteric acid (macrocyclic ionic GC), gadodiamide (linear nonionic GC) or saline, and sacrificed at PND 25. Gadodiamide induced mortality, alopecia and hyperpigmentation of dorsal skin. Two gadodiamide-treated rats presented severe epidermal and dermal lesions. No abnormal signs were detected following administration of gadoteric acid. Higher tissue gadolinium concentrations were found in the gadodiamide group compared to the gadoteric acid group. Dissociation of gadodiamide was observed in skin and liver, with the presence of dissociated and soluble gadolinium. In conclusion, repeated administration of gadoteric acid was well tolerated by juvenile rats. In contrast, gadodiamide induced significant toxicity and more marked tissue gadolinium retention (at least partly in the dissociated and soluble form).