Toxicological Safety Evaluation of Gadobutrol

Wack, Christiane; Steger‐Hartmann, Thomas; Mylecraine, Louis; Hofmeister, Rainer

doi:10.1097/rli.0b013e318263f128

Cited by 22 publications

(19 citation statements)

References 25 publications

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“…It is unclear why elevated Gd levels were determined in the kidneys after gadoterate and gadobutrol injections, but it may reflect vacuolization in the cytoplasm of the proximal tubular epithelial cells and the subsequent entrapment of GBCA molecules. This phenomenon has been observed previously after repeated administrations of gadobutrol to rats at intermediate to high doses, and, importantly, was not shown to have any cytotoxic degenerative effects on cell organelles . Reasons for the differences in measured Gd levels may reflect differences in the physicochemical characteristics, in particular viscosity, of the GBCAs.…”

Section: Discussionsupporting

confidence: 78%

Differences in gadolinium retention after repeated injections of macrocyclic MR contrast agents to rats

Bussi

Coppo

Botteron

et al. 2017

Magnetic Resonance Imaging

110

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PurposeTo compare the levels of gadolinium in the blood, cerebrum, cerebellum, liver, femur, kidneys, and skin after multiple exposure of rats to the macrocyclic gadolinium‐based contrast agents (GBCAs) gadoterate, gadobutrol, and gadoteridol.Materials and MethodsFifty male Wistar Han rats were randomized to three exposure groups (n = 15 per group) and one control group (n = 5). Animals in the exposure groups received a total of 20 GBCA administrations (four administrations per week for 5 consecutive weeks) at a dose of 0.6 mmol/kg bodyweight. After a 28‐day recovery period animals were sacrificed and the blood and tissues harvested for determination of gadolinium (Gd) levels. Gd determination was performed by inductively coupled plasma mass spectrometry (ICP‐MS).ResultsAfter 28 days' recovery no Gd was found in the blood, liver, or skin of any animal in any group. Significantly lower levels of Gd were noted with gadoteridol compared to gadoterate and gadobutrol in the cerebellum (0.150 ± 0.022 vs. 0.292 ± 0.057 and 0.287 ± 0.056 nmol/g, respectively; P < 0.001), cerebrum (0.116 ± 0.036 vs. 0.250 ± 0.032 and 0.263 ± 0.045 nmol/g, respectively; P < 0.001), and kidneys (25 ± 13 vs. 139 ± 88 [P < 0.01] and 204 ± 109 [P < 0.001], respectively). Higher levels of Gd were noted in the femur (7.48 ± 1.37 vs. 5.69 ± 1.75 and 8.60 ± 2.04 nmol/g, respectively) with significantly less Gd determined for gadoterate than for gadobutrol (P < 0.001) and gadoteridol (P < 0.05).ConclusionDifferences exist between macrocyclic agents in terms of their propensity to accumulate in tissues. The observed differences in Gd concentration point to differences in GBCA washout rates in this setting and in this experimental model, with gadoteridol being the GBCA that is most efficiently removed from both cerebral and renal tissues. Level of Evidence: 2 Technical Efficacy: Stage 5J. Magn. Reson. Imaging 2018;47:746–752.

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Section: Discussionsupporting

confidence: 78%

Differences in gadolinium retention after repeated injections of macrocyclic MR contrast agents to rats

Bussi

Coppo

Botteron

et al. 2017

Magnetic Resonance Imaging

110

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“…This was investigated by Takahashi [76], Ray [77], Wack [31]. Studies on primary cultured rat cortical neurons indicated toxic influence of gadolinium chloride on cell viability and connected it with dysfunction of the mitochondria followed by production of free radicals, decrease in ATP level and release of cyt C which led to cell death [78].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, the neurotoxicity of parallel or sequential application of ICG with Gd-based contrast agent (Gadovist) was not yet studied. In this paper we report on results of the study focused on neuronal ICG toxicity used alone and in combination with a rather nontoxic contrast agent -Gadovist [31], which forming a the mixture with ICG may change its properties and toxicity. These studies were performed using cerebellar granule cells (CGC) culture model and spectroscopies -absorption and NMR.…”

Section: Introductionmentioning

confidence: 99%

Neurotoxic effects of indocyanine green -cerebellar granule cell culture viability study

Toczyłowska

Ziemińska

Goch

et al. 2014

Biomed. Opt. Express

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Abstract:The aim of this study was to examine neurotoxicity indocyanine green (ICG). We assessed viability of primary cerebellar granule cell culture (CGC) exposed to ICG to test two mechanisms that could be the first triggers causing neuronal toxicity: imbalance in calcium homeostasis and the degree of oligomerization of ICG molecules. We have observed this imbalance in CGC after exposure to 75-125μΜ ICG and dose and application sequence dependent protective effect of Gadovist on surviving neurons in vitro when used with ICG. Spectroscopic studies suggest the major cause of toxicity of the ICG is connected with oligomers formation. ICG at concentration of 25 μM (which is about 4 times higher than the highest concentration of ICG in the brain applied in in-vivo human studies) is not neurotoxic in the cell culture. Orlock, and C. A. Puliafito, "Adverse reactions due to indocyanine green," Ophthalmology 101(3), 529-533 (1994). 2. B. F. Hochheimer, "Angiography of the retina with indocyanine green," Arch. Ophthalmol. 86(5), 564-565 (1971). 3. J. Fishbaugh, "Retina: indocyanine green (ICG) angiography," Insight 19(3), 30-32 (1994). 4. J. Caesar, S. Shaldon, L. Chiandussi, L. Guevara, and S. Sherlock, "The use of indocyanine green in the measurement of hepatic blood flow and as a test of hepatic function," Clin. Sci. 21, 43-57 (1961). 5. A. El-Desoky, A. M. Seifalian, M. Cope, D. T. Delpy, and B. R. Davidson, "Experimental study of liver dysfunction evaluated by direct indocyanine green clearance using near infrared spectroscopy," Br. J. Surg. 1005-1011 (1999). 6. T. Ishizawa, N. Fukushima, J. Shibahara, K. Masuda, S. Tamura, T. Aoki, K. Hasegawa, Y. Beck, M. Fukayama, and N. Kokudo, "Real-time identification of liver cancers by using indocyanine green fluorescent imaging," Cancer 115(11), 2491-2504 (2009 4998-5003 (2006). 17. T. L. Jackson, "Indocyanine green accused," Br. J. Ophthalmol. 89(4), 395-396 (2005). Reson. Imaging 14(6), 619-623 (1996). 77. D. E. Ray, J. B. Cavanagh, C. C. Nolan, and S. C. Williams, "Neurotoxic effects of gadopentetate dimeglumine: behavioral disturbance and morphology after intracerebroventricular injection in rats," AJNR Am. J. Neuroradiol. 17(2), 365-373 (1996). 78. X. Feng, Q. Xia, L. Yuan, X. Yang, and K. Wang, "Impaired mitochondrial function and oxidative stress in rat cortical neurons: implications for gadolinium-induced neurotoxicity," Neurotoxicology 31(4), 391-398 (2010). 79. M. P. Mattson and Y. Goodman, "Different amyloidogenic peptides share a similar mechanism of neurotoxicity involving reactive oxygen species and calcium," Brain Res. 676(1), 219-224 (1995). 86(8),

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“…Of note, we will employ the gadolinium-based contrast agent gadobutrol (Gadovist/Gadavist ® , Bayer Pharma AG, Berlin, Germany) in a non-toxic chelated preparation which exhibits negligible protein binding, distributes in extracellular space only, and is rapidly excreted via the renal pathway. It is widely used in humans to detect hepatic lesions or liver metastases respectively and well tolerated following intravenous injection either of a diagnostic single or repeated doses, with no relevant toxicity to the liver in either humans or rodents [47–49]. …”

Section: Discussionmentioning

confidence: 99%

Increased growth of colorectal liver metastasis following partial hepatectomy

Krause

Flikweert

Monin

et al. 2013

Clin Exp Metastasis

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Nearly 50 % of colorectal cancer (CRC) patients develop liver metastases with liver resection being the only option to cure patients. Residual micrometastases or circulating tumor cells are considered a cause of tumor relapse. This work investigates the influence of partial hepatectomy (PH) on the growth and molecular composition of CRC liver metastasis in a syngeneic rat model. One million CC531 colorectal tumor cells were implanted via the portal vein in WAG/Rij rats followed by a 30 % PH a day later. Control groups either received tumor cells followed by a sham-operation or were injected with a buffer solution followed by PH. Animals were examined with magnetic resonance imaging (MRI) and liver tissues were processed for immunolabeling and PCR analysis. One-third PH was associated with an almost threefold increase in relative tumor mass (MRI volumetry: 2.8-fold and transcript levels of CD44: 2.3-fold). Expression of molecular markers for invasiveness and aggressiveness (CD49f, CXCR4, Axin2 and c-met) was increased following PH, however with no significant differences when referring to the relative expression levels (relating to tumor mass). Liver metastases demonstrated a significantly higher proliferation rate (Ki67) 2 weeks following PH and cell divisions also increased in the surrounding liver tissue. Following PH, the stimulated growth of metastases clearly exceeded the compensation in liver volume with long-lasting proliferative effects. However, the distinct tumor composition was not influenced by liver regeneration. Future investigations should focus on the inhibition of cell cycle (i.e. systemic therapy strategies, irradiation) to hinder liver regeneration and therefore restrain tumor growth.

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Toxicological Safety Evaluation of Gadobutrol

Abstract: Gadobutrol was well tolerated with high safety margins between the single diagnostic dose of 0.1 mmol/kg in humans and the doses showing effects in animal studies.

Cited by 22 publications

References 25 publications

Differences in gadolinium retention after repeated injections of macrocyclic MR contrast agents to rats

Differences in gadolinium retention after repeated injections of macrocyclic MR contrast agents to rats

Neurotoxic effects of indocyanine green -cerebellar granule cell culture viability study

Increased growth of colorectal liver metastasis following partial hepatectomy

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