Michigan State University, Department of Radiology, East Lansing, Michigan.
Michigan State University Institute of Quantitative Health Science and Engineering, East Lansing, Michigan.
Magn Reson Med. 2019 Jul;82(1):387-394. doi: 10.1002/mrm.27730. Epub 2019 Mar 15.
While rodents are the primary animal models for contrast agent evaluation, rodents can potentially misrepresent human organ clearance of newly developed contrast agents. For example, gadolinium (Gd)-BOPTA has ~50% hepatic clearance in rodents, but ~5% in humans. This study demonstrates the benefit of chimeric mice expressing human hepatic OATPs (organic anion-transporting polypeptides) to improve evaluation of novel contrast agents for clinical use.
FVB (wild-type) and OATP1B1/1B3 knock-in mice were injected with hepatospecific MRI contrast agents (Gd-EOB-DTPA, Gd-BOPTA) and nonspecific Gd-DTPA. T -weighted dynamic contrast-enhanced MRI was performed on mice injected intravenously. Hepatic MRI signal enhancement was calculated per time point. Mass of gadolinium cleared per time point and percentage elimination by means of feces and urine were also measured.
Following intravenous injection of Gd-BOPTA in chimeric OATP1B1/1B3 knock-in mice, hepatic MRI signal enhancement and elimination by liver was more reflective of human hepatic clearance than that measured in wild-type mice. Gd-BOPTA hepatic MRI signal enhancement was reduced to 22% relative to wild-type mice. Gd-BOPTA elimination in wild-type mice was 83% fecal compared with 32% fecal in chimeric mice. Hepatic MRI signal enhancement and elimination for Gd-EOB-DTPA and Gd-DTPA were similar between wild-type and chimeric cohorts.
Hepatic MRI signal enhancement and elimination of Gd-EOB-DTPA, Gd-BOPTA, and Gd-DTPA in chimeric OATP1B1/1B3 knock-in mice closely mimics that seen in humans. This study provides evidence that the chimeric knock-in mouse is a more useful screening tool for novel MRI contrast agents destined for clinical use as compared to the traditionally used wild-type models.
虽然啮齿动物是评估对比剂的主要动物模型，但它们可能无法准确反映新开发的对比剂在人体器官中的清除情况。例如，钆（Gd）-BOPTA 在啮齿动物中有50%的肝脏清除率，但在人类中只有5%。本研究证明了表达人肝有机阴离子转运多肽（organic anion-transporting polypeptides，OATPs）的嵌合小鼠有助于改善用于临床的新型对比剂的评估。
FVB（野生型）和 OATP1B1/1B3 基因敲入小鼠分别静脉注射肝特异性 MRI 对比剂（Gd-EOB-DTPA、Gd-BOPTA）和非特异性 Gd-DTPA。对静脉注射的小鼠进行 T1 加权动态对比增强 MRI。根据每个时间点计算肝 MRI 信号增强。还测量每个时间点清除的镧系元素质量以及通过粪便和尿液的消除百分比。
在嵌合 OATP1B1/1B3 基因敲入小鼠中静脉注射 Gd-BOPTA 后，肝 MRI 信号增强和肝脏清除率更能反映人类肝脏清除率，而不是野生型小鼠。Gd-BOPTA 在野生型小鼠中的肝 MRI 信号增强降低至 22%，而在嵌合小鼠中降低至 32%。Gd-BOPTA 在野生型小鼠中的消除率为 83%通过粪便，而嵌合小鼠中为 32%。Gd-EOB-DTPA 和 Gd-DTPA 的肝 MRI 信号增强和消除在野生型和嵌合型小鼠中相似。
嵌合 OATP1B1/1B3 基因敲入小鼠中 Gd-EOB-DTPA、Gd-BOPTA 和 Gd-DTPA 的肝 MRI 信号增强和消除与人类非常相似。本研究提供的证据表明，与传统使用的野生型模型相比，嵌合基因敲入小鼠是一种更有用的新型 MRI 对比剂筛选工具，可用于临床应用。
