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.
Guerbet, Research Division, Aulnay-sous-Bois, France. Electronic address: nathalie.fretellier@guerbet-group.com.
Nathalie
N
Fretellier
Guerbet, Research Division, Aulnay-sous-Bois, France.
Mariem
M
Salhi
Department of Pathology, Regensburg University Hospital, Regensburg, Germany.
Josef
J
Schroeder
Department of Pathology, Regensburg University Hospital, Regensburg, Germany.
Heiko
H
Siegmund
Guerbet, Research Division, Aulnay-sous-Bois, France.
Thibaut
T
Chevalier
Department of Pathology, Hôpital Européen Georges Pompidou, Paris, France; INSERM U970, Department of Pathology, Hôpital Européen Georges Pompidou, Paris, France.
Patrick
P
Bruneval
Guerbet, Research Division, Aulnay-sous-Bois, France.
Gaëlle
G
Jestin-Mayer
Guerbet, Research Division, Aulnay-sous-Bois, France.
Francette
F
Delaloge
Guerbet, Research Division, Aulnay-sous-Bois, France.
Cécile
C
Factor
Guerbet, Research Division, Aulnay-sous-Bois, France.
Jean-François
JF
Mayer
Guerbet, Research Division, Aulnay-sous-Bois, France.
Jean-Michel
JM
Fabicki
Guerbet, Research Division, Aulnay-sous-Bois, France.
Caroline
C
Robic
Guerbet, Research Division, Aulnay-sous-Bois, France.
Bruno
B
Bonnemain
Guerbet, Research Division, Aulnay-sous-Bois, France.
Jean-Marc
JM
Idée
Guerbet, Research Division, Aulnay-sous-Bois, France.
Claire
C
Corot
D000818:Animals; D002614:Chelating Agents / Q000493:pharmacokinetics*; D002626:Chemistry, Pharmaceutical; D003287:Contrast Media / Q000493:pharmacokinetics*; D005269:Femur / Q000378:metabolism; D005682:Gadolinium / Q000097:blood / Q000493:pharmacokinetics*; D006571:Heterocyclic Compounds / Q000097:blood / Q000493:pharmacokinetics*; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism; D009942:Organometallic Compounds / Q000097:blood / Q000493:pharmacokinetics*; D017208:Rats, Wistar; D051437:Renal Insufficiency / Q000378:metabolism*; D012867:Skin / Q000187:drug effects / Q000378:metabolism
D002614:Chelating Agents; D003287:Contrast Media; D006571:Heterocyclic Compounds; D009942:Organometallic Compounds; C050823:gadolinium 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetate; D005682:Gadolinium
Contrast agents; Drug impurities; Gadolinium; Gadolinium chelates; Magnetic resonance imaging; Pharmaceutical solution