在高胆红素血症条件下亲脂性对亚氨基二乙酸衍生物肝胆特性的影响。

The effect of lipophilicity on the hepatobiliary properties of iminodiacetic acid derivatives in the conditions of hyperbilirubinemia.

作者信息

Brborić J, Jovanović M S, Vranješ-Đurić S, Cudina O, Marković B, Vladimirov S

机构信息

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, Belgrade, Serbia.

出版信息

Appl Radiat Isot. 2013 Apr;74:31-5. doi: 10.1016/j.apradiso.2012.12.014. Epub 2013 Jan 3.

DOI:10.1016/j.apradiso.2012.12.014

PMID:23353095

Abstract

The partition coefficients (log P) of theoretically possible alkyliodinated iminodiacetic acid (IDA) derivatives and commercial IDA derivatives were calculated using two computer programs: ChemSketch Log P and ChemOffice Ultra. Newly synthesized ligands (DIETHYLIODIDA and DIISOPROPYLIODIDA) with the highest calculated log P were labeled with technetium-99m. The biodistribution and the influence of bilirubin on their biokinetics were investigated in rats and compared to corresponding results for commercial (99m)Tc-BROMIDA. Log P of (99m)Tc-complexes of synthesized ligands were determined experimentally as well as the protein binding. In comparison to (99m)Tc-BROMIDA, (99m)Tc-DIETHYLIODIDA has: (a) better biliary excretion (2.76±0.15%ID/g versus 1.83±0.10%ID/g); (b) faster hepatic clearance (2.90±0.21%ID/g versus 7.47±0.70%ID/g) and decreased biliary excretion (for 14% versus 22%) in conditions of hyperbilirubinemia after 15min. It is proved that (99m)Tc-DIISOPROPYLIODIDA has a prolonged hepatic transit time and decreased biliary excretion.

摘要

使用ChemSketch Log P和ChemOffice Ultra这两个计算机程序，计算了理论上可能的烷基碘化亚氨基二乙酸（IDA）衍生物和市售IDA衍生物的分配系数（log P）。计算出log P最高的新合成配体（二乙基碘化IDA和二异丙基碘化IDA）用锝-99m进行标记。在大鼠中研究了它们的生物分布以及胆红素对其生物动力学的影响，并与市售（99m）Tc-溴米多的相应结果进行比较。通过实验测定了合成配体的（99m）Tc配合物的log P以及蛋白质结合情况。与（99m）Tc-溴米多相比，（99m）Tc-二乙基碘化IDA具有：（a）更好的胆汁排泄（2.76±0.15%ID/g对1.83±0.10%ID/g）；（b）在高胆红素血症15分钟后的情况下，肝脏清除更快（2.90±0.21%ID/g对7.47±0.70%ID/g）且胆汁排泄减少（分别为14%对22%）。已证明（99m）Tc-二异丙基碘化IDA具有延长的肝脏通过时间和减少的胆汁排泄。