MR and CT Contrast Media Research, Bayer AG, Berlin, Germany.
Invest Radiol. 2019 Feb;54(2):76-82. doi: 10.1097/RLI.0000000000000522.
This study investigated the potential effect of the chelating agent calcium trisodium pentetate (Ca-DTPA) on the urinary excretion of gadolinium and the subsequent elimination of gadolinium (Gd) in the brain after a single intravenous administration of either a linear (gadodiamide) or a macrocyclic (gadobutrol) Gd-based contrast agent in rats.
Rats received either a single injection of gadodiamide or gadobutrol (1.8 mmol/kg, each) or saline (n = 18 per group). Seven weeks after the injection, 6 animals of each group were killed before the treatment period. From the remaining 12 animals, 6 received either 3 intravenous injections of Ca-DTPA (180 μmol/kg) or saline. Urine was collected daily for 3 days after each infusion. Gadolinium measurements by ICP-MS were performed in urine and tissue samples.
In animals that initially received the linear gadodiamide, Ca-DTPA infusion increased the urinary excretion of Gd by a factor of 10 (cumulative amount of 114 ± 21 nmol Gd vs 10 ± 4 nmol Gd after saline infusion, P ≤ 0.0001). In contrast, animals that received the macrocyclic gadobutrol exhibited a higher spontaneous urinary excretion of Gd (33 ± 12 nmol after saline infusion) and Ca-DTPA had no impact (30 ± 11 nmol Gd, P = 0.68).The urinary excretion of Gd was associated with Gd brain content. Seven weeks after the initial Gd-based contrast agent administration, a total amount of 0.74 ± 0.053 nmol Gd was quantified in the brain after administration of gadodiamide. The Gd brain burden was partially reduced at the end of the treatment period in the animals that were repeatedly infused with Ca-DTPA (0.56 ± 0.13 nmol Gd, P = 0.009) but not with saline (0.66 ± 0.081 nmol, P = 0.32). In contrast, the total amount of macrocyclic gadobutrol measured in the brain was lower (0.11 ± 0.029 nmol Gd) and still spontaneously cleared during the 3-week saline infusion period (0.057 ± 0.019 nmol Gd (P = 0.003). Gadolinium quantified in the brain after infusions with Ca-DTPA did not differ from saline-infused animals (0.049 ± 0.014 nmol Gd).
Administration of the chelating agent Ca-DTPA 7 weeks after injection of linear gadodiamide induced relevant urinary Gd excretion. In parallel, the Gd amount in the brain tissue decreased. This indicates a dechelated pool among the chemical Gd forms present in the rat brain after linear gadodiamide administration that can be mobilized by chelation with Ca-DTPA. In contrast, Ca-DTPA did not mobilize Gd in animals that received macrocyclic gadobutrol, indicating that the Gd measured is intact gadobutrol.
本研究旨在探讨螯合剂钙三钠五乙酸（Ca-DTPA）对大鼠单次静脉注射线性（钆喷酸葡胺）或大环（钆布醇）Gd 基造影剂后尿中 Gd 排泄和随后脑内 Gd 清除的潜在影响。
大鼠分别接受单次注射钆喷酸葡胺或钆布醇（1.8mmol/kg，每组 18 只）或生理盐水（每组 18 只）。注射后 7 周，每组 6 只动物在治疗前处死。其余 12 只动物中，6 只接受 3 次静脉注射 Ca-DTPA（180μmol/kg）或生理盐水。每次输注后连续 3 天收集尿液。通过 ICP-MS 对尿液和组织样本进行 Gd 测量。
最初接受线性钆喷酸葡胺的动物中，Ca-DTPA 输注使 Gd 的尿排泄增加了 10 倍（累积量 114±21nmol Gd 与盐水输注后 10±4nmol Gd 相比，P≤0.0001）。相比之下，接受大环钆布醇的动物表现出更高的自发 Gd 尿排泄（盐水输注后 33±12nmol Gd），而 Ca-DTPA 没有影响（30±11nmol Gd，P=0.68）。Gd 的尿排泄与 Gd 脑含量有关。在初始 Gd 基造影剂给药后 7 周，给予钆喷酸葡胺后大脑中定量为 0.74±0.053nmol Gd。在反复接受 Ca-DTPA 输注的动物中，治疗期末 Gd 的脑负担部分减少（0.56±0.13nmol Gd，P=0.009），但在接受生理盐水输注的动物中没有减少（0.66±0.081nmol，P=0.32）。相比之下，在 3 周生理盐水输注期间，测量的脑内大环钆布醇总量较低（0.11±0.029nmol Gd）且仍自发清除（0.057±0.019nmol Gd（P=0.003）。接受 Ca-DTPA 输注后在脑内定量的 Gd 与接受生理盐水输注的动物无差异（0.049±0.014nmol Gd）。
在注射线性钆喷酸葡胺 7 周后给予螯合剂 Ca-DTPA 诱导了相关的尿 Gd 排泄。同时，脑组织中的 Gd 量减少。这表明在大鼠脑内注射线性钆喷酸葡胺后，存在化学 Gd 形式的去螯合池，可通过与 Ca-DTPA 螯合来动员。相比之下，Ca-DTPA 未动员接受大环钆布醇的动物中的 Gd，表明测量的 Gd 是完整的钆布醇。
