Invest Radiol. 2018 Mar;53(3):167-172. doi: 10.1097/RLI.0000000000000423.
The aim of the study was to explore the role of the stability of metal complexes in the processes that lead to the metal retention in the brain and other tissues of mice administered with lanthanides-based contrast agents. This issue was tackled by the simultaneous injection of gadolinium (Gd)-diethylentriamminopentaacetate (DTPA) and lanthanum-DTPA, which have the same charge and structure but differ in their thermodynamic stability by 3 orders of magnitude.
A total of 20 healthy BALB/c mice were administered by a single intravenous injection with a dose consisting of 0.6 mmol La-DTPA/kg and 0.6 mmol Gd-DTPA/kg. Then the animals were killed at different time points: 4, 24, 48, and 96 hours (5 mice each group).In an additional protocol, 5 mice were administered with 9 doses of 0.3 mmol La-DTPA/kg and 0.3 mmol of Gd-DTPA/kg every 2 days over a period of 3 weeks. The sacrifice time was set to 3 weeks after the last administration. After sacrifice, the Gd and La content in liver, spleen, kidney, muscle, cerebrum, cerebellum, bone, eye, skin, blood, and urine was determined by inductively coupled plasma-mass spectrometry.
A general decrease in the content of both the lanthanides was observed upon delaying the sacrifice time. At relatively short times after the injection (up to 96 hours), in the spleen, kidney, muscle, skin, and eye, almost the same content of La and Gd was detected, whereas in the cerebrum, cerebellum, bones, and liver, the amount of retained La decreased much slower than that of Gd, yielding a progressive increase in La/Gd ratio. The amount of retained La in the various tissues 21 days after the last of 9 administrations of La-DTPA and Gd-DTPA was always significantly higher than that of Gd. The concentration of both La and Gd decreased rapidly both in blood and in urine samples.
The departure from the 1:1 ratio in the amounts of La and Gd determined in the investigated tissues has been used to gain information on the role of the complex stability and "wash-out" kinetics. The behavior of the less s` La-DTPA highlights processes occurring for Gd-DTPA at a slower rate.The herein obtained results support the view that most of the La/Gd retained in the brain arises from the intact chelate that has extravasated immediately after the intravenous administration. Long-term deposition of metal ions from internal reservoirs seems particularly relevant for liver and spleen.
本研究旨在探讨金属配合物稳定性在导致镧系元素基造影剂给药后小鼠脑和其他组织中金属滞留过程中的作用。通过同时注射具有相同电荷和结构但热力学稳定性相差 3 个数量级的钆（Gd）-二乙三胺五乙酸（DTPA）和镧-DTPA 来解决这个问题。
总共 20 只健康 BALB/c 小鼠通过单次静脉注射给予剂量为 0.6mmol La-DTPA/kg 和 0.6mmol Gd-DTPA/kg。然后，动物在不同时间点处死：4、24、48 和 96 小时（每组 5 只）。在一个附加方案中，5 只小鼠每隔 2 天接受 9 次 0.3mmol La-DTPA/kg 和 0.3mmol Gd-DTPA/kg 的剂量，持续 3 周。处死时间设定为最后一次给药后 3 周。处死动物后，通过电感耦合等离子体质谱法测定肝、脾、肾、肌肉、脑、小脑、骨、眼、皮肤、血和尿中的 Gd 和 La 含量。
随着处死时间的延迟，两种镧系元素的含量普遍下降。在注射后相对较短的时间内（最多 96 小时），在脾、肾、肌肉、皮肤和眼组织中，检测到的 La 和 Gd 含量几乎相同，而在脑、小脑、骨和肝组织中，La 的滞留量下降速度明显慢于 Gd，导致 La/Gd 比值逐渐增加。最后 9 次 La-DTPA 和 Gd-DTPA 给药后 21 天，各组织中滞留的 La 量始终明显高于 Gd。血样和尿样中 La 和 Gd 的浓度均迅速下降。
在所研究的组织中确定的 La 和 Gd 量偏离 1:1 比例，用于获取有关配合物稳定性和“冲洗”动力学作用的信息。较少的 La-DTPA 的行为突出了在较慢速度下发生的 Gd-DTPA 过程。本文获得的结果支持这样的观点，即脑内保留的大部分 La/Gd 来自静脉给药后立即外渗的完整螯合物。来自内部储库的金属离子的长期沉积似乎对肝和脾特别重要。
