From the Department of MR and CT Contrast Media Research (J.B., J.L., G.J., T.F., H.P.) and Research and Pre-Clinical Statistics Group (H.F.U.), Bayer, Müllerstraße 178, 13353 Berlin, Germany; Department of In Vivo/Radioanalytics (A.T.) and Department of Bioanalytics LC-MS 3 & MALDI (U.T.), Bayer, Wuppertal, Germany; Department of Neuropharmacology, QPS Austria, Grambach, Austria (J.N., M.P.); and External Corporate Employment Resources, Bayer U.S., Whippany, NJ (T.B.).
Radiology. 2024 Jan;310(1):e231984. doi: 10.1148/radiol.231984.
Background The presence of gadolinium traces in the skin after administration of gadolinium-based contrast agents (GBCAs) raised safety concerns regarding a potential association with small fiber neuropathy (SFN). Purpose To investigate signs of SFN in rat foot pads by quantification of the intraepidermal nerve fiber density (IENFD) after multiple GBCA administrations and to evaluate gadolinium concentration, chemical species, and clearance. Materials and Methods Fifty rats received eight intravenous injections of either gadodiamide, gadobutrol, gadoterate, gadoteridol (8 × 0.6 mmol per kilogram of body weight), or saline (1.2 mL per kilogram of body weight), within 2 weeks and were sacrificed 5 days or 5 weeks after the last injection. IENFD was determined with protein gene product (PGP) 9.5 immunofluorescent staining and blinded and automated image analysis. The gadolinium and GBCA concentrations were measured with inductively coupled plasma mass spectrometry (ICP-MS), laser ablation ICP-MS, and matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI). values were calculated using linear contrasts of model analysis. Results The IENFD (measured as geometric mean [SD] and in number of nerve fibers per millimeter of epidermis) was not significantly altered after 5 days (saline, 8.4 [1.1]; gadobutrol, 9.7 [1.2]; gadoterate, 9.2 [1.2]; gadoteridol, 9.9 [1.3]; gadodiamide, 10.5 [1.2]) or 5 weeks (saline, 19.7 [1.4]; gadobutrol, 16.4 [1.6]; gadoterate, 14.3 [1.6]; gadoteridol, 22.2 [1.8]; gadodiamide, 17.9 [1.4]). Gadolinium skin concentrations were highest for gadodiamide after 5 days (16.0 nmol/g [1.1]) and 5 weeks (10.6 nmol/g [1.2], -33%). Macrocyclic agents were lower at 5 days (gadoteridol, 2.6 nmol/g [1.2]; gadobutrol, 2.7 nmol/g [1.1]; and gadoterate, 2.3 nmol/g [1.2]) and efficiently cleared after 5 weeks (gadoteridol, -95%; gadobutrol and gadoterate, -96%). The distribution of gadolinium and IENF did not visually overlap. For macrocyclic agents, gadolinium was found in sweat glands and confirmed to be intact chelate. Conclusion There were no signs of SFN in rat foot pads using multiple dosing regimens at two time points after administration of GBCAs. Macrocyclic GBCAs exhibited lower levels of gadolinium in the skin and were effectively eliminated within 5 weeks compared with linear gadodiamide, and intact macrocyclic GBCA was detected in sweat glands. © RSNA, 2024 See also the editorial by Clement in this issue.
背景 在给予钆基造影剂（GBCA）后皮肤中存在钆痕迹，引发了对与小纤维神经病（SFN）潜在关联的安全性担忧。目的 通过定量测定表皮内神经纤维密度（IENFD），研究大鼠足底垫中 SFN 的迹象，评估钆浓度、化学物质和清除率。材料与方法 50 只大鼠在 2 周内接受 8 次静脉注射，分别为钆喷酸葡胺、钆布醇、钆特酸葡胺、钆特醇（8×0.6mmol/kg 体重）或生理盐水（1.2mL/kg 体重），最后一次注射后 5 天或 5 周处死。使用蛋白基因产物（PGP）9.5 免疫荧光染色和盲法、自动化图像分析来确定 IENFD。使用电感耦合等离子体质谱法（ICP-MS）、激光烧蚀 ICP-MS 和基质辅助激光解吸/电离质谱成像（MALDI MSI）测量钆和 GBCA 浓度。使用线性对比模型分析计算 值。结果 5 天后（生理盐水，8.4[1.1]；钆布醇，9.7[1.2]；钆特酸葡胺，9.2[1.2]；钆特醇，9.9[1.3]；钆喷酸葡胺，10.5[1.2]）和 5 周后（生理盐水，19.7[1.4]；钆布醇，16.4[1.6]；钆特酸葡胺，14.3[1.6]；钆特醇，22.2[1.8]；钆喷酸葡胺，17.9[1.4]），IENFD（以几何平均值[SD]和每毫米表皮的神经纤维数表示）无明显变化。5 天后（钆喷酸葡胺，16.0nmol/g[1.1]）和 5 周后（钆喷酸葡胺，10.6nmol/g[1.2]，-33%），钆在皮肤中的浓度最高。大环类化合物在 5 天时较低（钆特醇，2.6nmol/g[1.2]；钆布醇，2.7nmol/g[1.1]；钆特酸葡胺，2.3nmol/g[1.2]），5 周后有效清除（钆特醇，-95%；钆布醇和钆特酸葡胺，-96%）。钆和 IENF 的分布在视觉上没有重叠。对于大环类化合物，在汗腺中发现了钆，证实其为完整的螯合物。结论 在给予 GBCA 后两个时间点，使用多种给药方案，大鼠足底垫未出现 SFN 迹象。与线性钆喷酸葡胺相比，大环类 GBCA 在皮肤中的钆水平较低，且在 5 周内有效清除，在汗腺中检测到完整的大环类 GBCA。
