From the Department of Research and Innovation, Imaging and Biological Research Division, Guerbet Group, BP57400, 95943 Roissy CDG, France (P.R., C.F., V.V., J.L., M.R., R.S., S.B., J.M.I., C.C.); and Institute of Inorganic and Analytical Chemistry, University of Münster, Münster, Germany (S.F., M.S., U.K.).
Radiology. 2018 Aug;288(2):424-433. doi: 10.1148/radiol.2018172746. Epub 2018 May 22.
Purpose To compare the long-term brain elimination kinetics and gadolinium species in healthy rats after repeated injections of the contrast agents gadodiamide (a linear contrast agent) or gadoterate (a macrocyclic contrast agent). Materials and Methods Nine-week-old rats received five doses of 2.4 mmol gadolinium per kilogram of body weight over 5 weeks and were followed for 12 months with T1-weighted MRI (n = 140 rats, corresponding to seven time points, two contrast agents, and 10 rats per group). Animals were sacrificed at 1 week, 1 month, and 2, 3, 4, 5, and 12 months after the last injection. Brain and plasma were sampled to determine the total gadolinium concentration by using inductively coupled plasma mass spectrometry (ICP-MS). For the cerebellum, gadolinium speciation analysis was performed after mild extraction at four time points (1 month and 3, 5, and 12 months after the last injection) by using size exclusion chromatography and hydrophilic interaction liquid chromatography, both coupled to ICP-MS. Tissue gadolinium kinetics were fitted to estimate the area under the curves and tissue elimination half-lives over the 12-month injection-free period. Results T1 hyperintensity of the deep cerebellar nuclei was observed only in gadodiamide-treated rats and remained stable from the 1st month after the last injection (the ratio of the signal intensity of the deep cerebellar nuclei to the signal intensity of the brain stem at 1 year: 1.101 ± 0.023 vs 1.037 ± 0.022 before injection, P < .001). Seventy-five percent of the total gadolinium detected after the last injection of gadodiamide (3.25 nmol/g ± 0.30) was retained in the cerebellum at 1 year (2.45 nmol/g ± 0.35), with binding of soluble gadolinium to macromolecules. No T1 hyperintensity was observed with gadoterate, consistent with a rapid, time-dependent washout of the intact gadolinium chelate down to background levels (0.07 nmol/g ± 0.03). Conclusion After repeated administration of gadodiamide, a large portion of gadolinium was retained in the brain, with binding of soluble gadolinium to macromolecules. After repeated injection of gadoterate, only traces of the intact chelated gadolinium were observed with time-dependent clearance. Online supplemental material is available for this article.
比较健康大鼠重复注射对比剂钆喷酸葡胺（一种线性对比剂）或钆特酸葡胺（一种大环对比剂）后的长期脑消除动力学和钆形态。
9 周龄大鼠在 5 周内接受 5 次 2.4mmol/kg 体重的剂量，并在最后一次注射后 12 个月内通过 T1 加权 MRI 进行随访（n = 140 只大鼠，对应 7 个时间点、2 种对比剂和每组 10 只大鼠）。在最后一次注射后 1 周、1 个月和 2、3、4、5 和 12 个月时处死动物。通过电感耦合等离子体质谱法（ICP-MS）测定脑和血浆中的总钆浓度，以确定总钆浓度。在最后一次注射后 1 个月和 3、5 和 12 个月时，对小脑进行轻度提取后，采用排阻色谱法和亲水相互作用液相色谱法对其进行分析，然后与 ICP-MS 联用，以进行钆形态分析。拟合组织中的钆动力学，以估计 12 个月无注射期间的曲线下面积和组织消除半衰期。
仅在接受钆喷酸葡胺治疗的大鼠中观察到深部小脑核的 T1 高信号，且从最后一次注射后 1 个月开始保持稳定（深部小脑核的信号强度与注射前的信号强度之比在 1 年内：1.101 ± 0.023 比 1.037 ± 0.022，P <.001）。最后一次注射钆喷酸葡胺后检测到的总钆的 75%（3.25nmol/g ± 0.30）在 1 年内保留在小脑内（2.45nmol/g ± 0.35），其中可溶性钆与大分子结合。在接受钆特酸葡胺治疗的大鼠中未观察到 T1 高信号，这与完整的钆螯合物的快速、时间依赖性清除至背景水平（0.07nmol/g ± 0.03）一致。
在重复给予钆喷酸葡胺后，大量的钆保留在脑内，其中可溶性钆与大分子结合。在重复注射钆特酸葡胺后，随着时间的推移，仅观察到痕量完整螯合的钆被清除。
在线补充材料可在本文中查看。
