Exogenous fluorescent tracer agents based on pegylated pyrazine dyes for real-time point-of-care measurement of glomerular filtration rate
Exogenous fluorescent tracer agents based on pegylated pyrazine dyes for real-time point-of-care measurement of glomerular filtration rate
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DOI：
10.1016/j.bmc.2012.03.015
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发表时间：
2012-04-15
影响因子：
3.5
通讯作者：
Dorshow, Richard B.
中科院分区：
文献类型：
--
作者：
Poreddy, Amruta R.;Neumann, William L.;Dorshow, Richard B.
新型吡嗪羧酰胺轴承亲水性聚（乙二醇）（PEG）部分的设计，合成，并评估作为荧光肾小球滤过率（GFR）示踪剂。其中，在PEG链中含有约48个环氧乙烷单元的化合物4d和5c表现出最有利的物理化学和肾清除特性。体外研究表明，这两种化合物具有较低的血浆蛋白结合率，这是肾脏排泄的必要条件。体内动物模型结果显示，4d和5c具有比碘酞酸盐（通常认为的金标准GFR试剂）更高的注射剂量的尿回收率。药代动力学研究表明，这两种化合物的血浆清除率与碘酞酸盐相当，但终末半衰期比碘酞酸盐更快（即更短）（可能是由于大分子尺寸和流体动力学体积导致的细胞外空间分布受限）。此外，4d和5c的血浆清除率在用丙磺舒阻断肾小管分泌途径后保持不变，丙磺舒是专门通过肾小球过滤建立清除率的必要条件。最后，通过大鼠模型中光学测量5c的药代动力学清除率证明了对此类化合物的非侵入性实时监测，这与示踪剂的血浆浓度密切相关。因此，4d和5c是有前途的候选翻译到临床作为外源性荧光示踪剂在实时点的护理监测GFR。(C)2012爱思唯尔有限公司保留所有权利。
Novel pyrazine carboxamides bearing hydrophilic poly(ethylene glycol) (PEG) moieties were designed, synthesized, and evaluated for use as fluorescent glomerular filtration rate (GFR) tracer agents. Among these, compounds 4d and 5c that contain about 48 ethylene oxide units in the PEG chain exhibited the most favorable physicochemical and renal clearance properties. In vitro studies show that these two compounds have low plasma protein binding, a necessary condition for renal excretion. In vivo animal model results show that 4d and 5c have a higher urine recovery of the injected dose than iothalamate (a commonly considered gold standard GFR agent). Pharmacokinetic studies show that these two compounds exhibit a plasma clearance equivalent to iothalamate, but with a faster (i.e. lower) terminal half-life than iothalamate (possibly from restricted distribution into the extracellular space due to large molecular size and hydrodynamic volume). Furthermore, the plasma clearance of 4d and 5c remained unchanged upon blockage of the tubular secretion pathway with probenecid, a necessary condition for establishment of clearance via glomerular filtration exclusively. Finally, noninvasive real-time monitoring of this class of compounds was demonstrated by pharmacokinetic clearance of 5c by optical measurements in rat model, which correlates strongly with plasma concentration of the tracer. Hence, 4d and 5c are promising candidates for translation to the clinic as exogenous fluorescent tracer agents in real-time point-of-care monitoring of GFR. (C) 2012 Elsevier Ltd. All rights reserved.