Pharmacokinetics and magnetic resonance imaging of biodegradable macromolecular blood-pool contrast agent PG-Gd in non-human primates: a pilot study.
Pharmacokinetics and magnetic resonance imaging of biodegradable macromolecular blood-pool contrast agent PG-Gd in non-human primates: a pilot study.
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DOI：
10.1002/cmmi.431
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发表时间：
2011-07
影响因子：
--
通讯作者：
Li, Chun
中科院分区：
文献类型：
--
作者：
Tian, Mei;Wen, Xiaoxia;Jackson, Edward F.;Ng, Chaan;Uthamanthil, Rajesh;Liang, Dong;Gelovani, Juri G.;Li, Chun
本研究的目的是评价聚（L-谷氨酸）-苄基-DTPA-Gd（PG-Gd），一种新的可生物降解的大分子磁共振成像造影剂，其在非人灵长类动物的药代动力学和MRI增强。在恒河猴中以0.01、0.02和0.08 mmol Gd/kg的静脉剂量进行研究。采用快速扰相梯度回波和快速自旋回波成像方案，在1.5T下采集T1加权图像。使用小分子造影剂Magnevist作为对照。PG-Gd在猴体内呈双指数分布。PG-Gd给药后2小时内的初始血药浓度远高于Magnevist。PG-Gd的高血药浓度与MR成像数据一致，显示PG-Gd在血池中循环延长。在注射三种剂量的造影剂后2小时，可清楚地观察到具有高血液灌注的血管和器官（心脏、肝脏和肾脏）的增强。当单次给药剂量从0.01 mmol/kg增加至0.08 mmol/kg时，观察到血药浓度-时间曲线下面积的增加比例大于增加比例。注射PG-Gd后2天，造影剂大部分从所有主要器官（包括肾脏）中清除。在0.08 mmol/kg剂量下，平均停留时间为15小时。在小鼠中观察到类似的药代动力学特征，平均滞留时间为5.4小时，稳态分布容积为85.5 mL/kg，表明药物主要分布在血液室中。基于该初步研究，在人体试验该药剂之前，需要进一步研究PG-Gd在啮齿动物和大型动物中的潜在全身毒性。
The purpose of this study was to evaluate poly(L-glutamic acid)-benzyl-DTPA-Gd (PG-Gd), a new biodegradable macromolecular magnetic resonance imaging contrast agent, for its pharmacokinetics and MRI enhancement in nonhuman primates. Studies were performed in rhesus monkeys at intravenous doses of 0.01, 0.02, and 0.08 mmol Gd/kg. T1-weighted MR images were acquired at 1.5T using fast spoiled gradient recalled echo and fast spin echo imaging protocols. The small-molecule contrast agent Magnevist was used as a control. PG-Gd in the monkey showed a bi-exponential disposition. The initial blood concentrations within 2 hours of PG-Gd administration were much higher than for those of Magnevist. The high blood concentration of PG-Gd was consistent with the MR imaging data, which showed prolonged circulation of PG-Gd in the blood pool. Enhancement of blood vessels and organs with a high blood perfusion (heart, liver, and kidney) was clearly visualized at 2 hours after contrast injection at the three doses used. A greater than proportional increase of the area under the blood concentration-time curve was observed when the administered single dose was increased from 0.01 mmol/kg to 0.08 mmol/kg. By 2 days after PG-Gd injection, the contrast agent was mostly cleared from all major organs, including kidney. The mean residence time was 15 hours at the 0.08 mmol/kg dose. A similar pharmacokinetic profile was observed in mice, with a mean residence time of 5.4 hours and a volume of distribution at steady-state of 85.5 mL/kg, indicating that the drug was mainly distributed in the blood compartment. Based on this pilot study, further investigations on potential systemic toxicity of PG-Gd in both rodents and large animals are needed before testing this agent in humans.
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