Sheu R S, Liu G C, Wang Y M, Jaw T S, Chen H M, Kuo Y T
Department of Radiology, Kaohsiung Medical College, Taiwan, Republic of China.
Kaohsiung J Med Sci. 1997 Feb;13(2):75-85.
Iron(III)-N, N'-ethylenebis[2-(2-hydroxy-5-phenyl)glycine] [Fe-(5-C2H5-EHPG)-] is a paramagnetic complex designed for use as a hepatobiliary agent. Test procedures included synthesis, characterization, toxicity evaluation, biodistribution and experiments for animal MR images. The dose of LD50 in acute toxicity test of Fe-(5-C2H5-EHPG)- in mice was 3.49 mmol/kg. 111In-(5-C2H5-EHPG)- biodistribution studies revealed that the activities were (4.78 +/- 0.97, 5.34 +/- 0.91, 4.53 +/- 0.35)%ID and (0.88 +/- 0.18, 0.99 +/- 0.17, 0.84 +/- 0.06)%ID/gm in the liver at time intervals of 10, 30 and 60 minutes after injection; (5.76 +/- 0.15, 5.75 +/- 0.15, 4.00 +/- 0.04)%ID and (0.49 +/- 0.03, 0.49 +/- 0.05, 0.34 +/- 0.01)%ID/gm in the blood; (1.27 +/- 0.91, 1.46 +/- 1.00, 1.52 +/- 0.46) %ID and (0.89 +/- 0.17, 1.02 +/- 0.18, 1.06 +/- 0.08)%ID/gm in the kidneys, respectively. The results of image enhancement correlated well to the biodistribution. Analysis of the MR images showed degrees of maximal parenchymal % increase of signal to noise ratio (S/N) was 42.09 +/- 3.59% for normal liver at 30 minutes postinjection, which exceeded the value of pathologic liver with bile duct obstruction 16 hours 17.26 +/- 6.6 %, 1 week 19.80 +/- 6.46% and 4 weeks 32.20 +/- 9.01%, respectively, and acute hepatitis 16.50% +/- 4.02%. Persistent enhancement plateau was documented up to 60 minutes after injection and normalized to precontrast value within 22 hours. The common duct was opacified at 10-15 minutes after injection of contrast agent. These results indicated that the Fe-(5-C2H5-EHPG)- could be rapidly extracted from the blood stream by the hepatocytes and excreted into the bile duct. The initial evaluation of Fe-(5-C2H5-EHPG)- demonstrated that Fe-(5-C2H5-EHPG)- was well suited for enhancement of normal liver parenchyma and was compromised with deterioration of liver function. However, the increase of the liver intensities in the animal model of the total biliary obstruction group normalized to precontrast value within 22 hours, which indicated that renal clearance as an effective alternative pathway for biliary excretion. In conclusion, these results indicate that Fe-(5-C2H5-EHPG)- has the potential of becoming a safe and reliable magnetopharmaceutical for the hepatobiliary system.
铁（III）-N，N'-亚乙基双[2-（2-羟基-5-苯基）甘氨酸][Fe-(5-C2H5-EHPG)-]是一种设计用作肝胆显像剂的顺磁性配合物。测试程序包括合成、表征、毒性评估、生物分布以及动物磁共振成像实验。Fe-(5-C2H5-EHPG)-在小鼠急性毒性试验中的半数致死剂量为3.49 mmol/kg。111In-(5-C2H5-EHPG)-生物分布研究表明，注射后10、30和60分钟时，肝脏中的放射性活度分别为（4.78±0.97、5.34±0.91、4.53±0.35）%注射剂量（ID）和（0.88±0.18、0.99±0.17、0.84±0.06）%ID/g；血液中的放射性活度分别为（5.76±0.15、5.75±0.15、4.00±0.04）%ID和（0.49±0.03、0.49±0.05、0.34±0.01）%ID/g；肾脏中的放射性活度分别为（1.27±0.91、1.46±1.00、1.52±0.46）%ID和（0.89±0.17、1.02±0.18、1.06±0.08）%ID/g。图像增强结果与生物分布密切相关。磁共振图像分析显示，注射后30分钟，正常肝脏实质信号噪声比（S/N）最大百分比增加值为42.09±3.59%，超过了胆管梗阻病理肝脏在16小时时的17.26±6.6%、1周时的19.80±6.46%、4周时的32.20±9.01%以及急性肝炎时的16.50±4.02%。注射后长达60分钟记录到持续增强平台期，并在22小时内恢复到注射前值。注射造影剂后10 - 15分钟，胆总管显影。这些结果表明，Fe-(5-C2H5-EHPG)-可被肝细胞迅速从血流中摄取并排泄到胆管。Fe-(5-C2H5-EHPG)-的初步评估表明，Fe-(5-C2H5-EHPG)-非常适合增强正常肝脏实质，且随着肝功能恶化而受损。然而，完全胆管梗阻组动物模型中肝脏强度的增加在22小时内恢复到注射前值，这表明肾脏清除作为胆汁排泄的有效替代途径。总之，这些结果表明Fe-(5-C2H5-EHPG)-有潜力成为一种安全可靠的肝胆系统磁性药物。
