Clearance of Gadolinium from the Brain with No Pathologic Effect after Repeated Administration of Gadodiamide in Healthy Rats: An Analytical and Histologic Study.
Purpose To measure the levels of gadolinium present in the rat brain 1 and 20 weeks after dosing with contrast agent and to determine if there are any histopathologic sequelae. Materials and Methods The study was approved by the GE Global Research Center Institutional Animal Care and Use Committee. Absolute gadolinium levels were quantified in the blood and brains of rats 1 week after dosing and 20 weeks after dosing with up to 20 repeat doses of gadodiamide (cumulative dose, 12 mmol per kilogram of body weight) by using inductively coupled plasma-mass spectrometry. Treatment groups (n = 6 rats per group) included low-dosage and high-dosage gadodiamide and osmolality-matched saline controls. Brain sections were submitted (blinded) for standard toxicology assessment per Registry of Industrial Toxicology Animal data guidelines. Analysis of variance and Mann-Whitney U tests with post hoc correction were used to assess differences in absolute gadolinium levels and percentage of injected dose, respectively. Results Dose-dependent low levels of gadolinium were detected in the brain, a mean ± standard deviation of 2.49 nmol per gram of brain tissue ± 0.30 or 0.00019% of the injected dose 1 week after dosing. This diminished by approximately 50% (to 1.38 nmol per gram of brain tissue ± 0.10 or 0.00011% of the injected dose) 20 weeks after dosing. As a percentage of injected dose, the levels of gadolinium measured were comparable between different doses, indicating that mechanisms of uptake and elimination were not saturated at the tested doses. There were no histopathologic findings associated with the levels of gadolinium measured. Conclusion Low levels of gadolinium are present in the brain after repeat dosing with gadodiamide, which is partially cleared over 20 weeks with no detectable neurotoxicity.
From GE Healthcare, The Grove Centre (GC18), White Lion Rd, Amersham HP7 9LL, England (A.P.L.S., P.M.E.); GE Global Research Centre, Niskayuna, NY (M.M., J.R., J.M.C., J.C., L.L., C.M.); and GE Healthcare, Life Sciences, Marlborough, Mass (M.G.H.).
Adrian P L
AP
Smith
From GE Healthcare, The Grove Centre (GC18), White Lion Rd, Amersham HP7 9LL, England (A.P.L.S., P.M.E.); GE Global Research Centre, Niskayuna, NY (M.M., J.R., J.M.C., J.C., L.L., C.M.); and GE Healthcare, Life Sciences, Marlborough, Mass (M.G.H.).
Michael
M
Marino
From GE Healthcare, The Grove Centre (GC18), White Lion Rd, Amersham HP7 9LL, England (A.P.L.S., P.M.E.); GE Global Research Centre, Niskayuna, NY (M.M., J.R., J.M.C., J.C., L.L., C.M.); and GE Healthcare, Life Sciences, Marlborough, Mass (M.G.H.).
Jeanette
J
Roberts
From GE Healthcare, The Grove Centre (GC18), White Lion Rd, Amersham HP7 9LL, England (A.P.L.S., P.M.E.); GE Global Research Centre, Niskayuna, NY (M.M., J.R., J.M.C., J.C., L.L., C.M.); and GE Healthcare, Life Sciences, Marlborough, Mass (M.G.H.).
Janell M
JM
Crowder
From GE Healthcare, The Grove Centre (GC18), White Lion Rd, Amersham HP7 9LL, England (A.P.L.S., P.M.E.); GE Global Research Centre, Niskayuna, NY (M.M., J.R., J.M.C., J.C., L.L., C.M.); and GE Healthcare, Life Sciences, Marlborough, Mass (M.G.H.).
Jason
J
Castle
From GE Healthcare, The Grove Centre (GC18), White Lion Rd, Amersham HP7 9LL, England (A.P.L.S., P.M.E.); GE Global Research Centre, Niskayuna, NY (M.M., J.R., J.M.C., J.C., L.L., C.M.); and GE Healthcare, Life Sciences, Marlborough, Mass (M.G.H.).
Lisa
L
Lowery
From GE Healthcare, The Grove Centre (GC18), White Lion Rd, Amersham HP7 9LL, England (A.P.L.S., P.M.E.); GE Global Research Centre, Niskayuna, NY (M.M., J.R., J.M.C., J.C., L.L., C.M.); and GE Healthcare, Life Sciences, Marlborough, Mass (M.G.H.).
Christine
C
Morton
From GE Healthcare, The Grove Centre (GC18), White Lion Rd, Amersham HP7 9LL, England (A.P.L.S., P.M.E.); GE Global Research Centre, Niskayuna, NY (M.M., J.R., J.M.C., J.C., L.L., C.M.); and GE Healthcare, Life Sciences, Marlborough, Mass (M.G.H.).
Mark G
MG
Hibberd
From GE Healthcare, The Grove Centre (GC18), White Lion Rd, Amersham HP7 9LL, England (A.P.L.S., P.M.E.); GE Global Research Centre, Niskayuna, NY (M.M., J.R., J.M.C., J.C., L.L., C.M.); and GE Healthcare, Life Sciences, Marlborough, Mass (M.G.H.).
Paul M
PM
Evans
D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000648:ultrastructure; D003287:Contrast Media / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D019786:Gadolinium DTPA / Q000493:pharmacokinetics*; D013058:Mass Spectrometry; D051381:Rats; D013054:Spectrophotometry, Atomic
D003287:Contrast Media; C064925:gadodiamide; D019786:Gadolinium DTPA