Reduced Renal Uptake of Various Radiopharmaceuticals with Sodium Paraaminohippurate Coadministration in a Rat Model

Marian Meckel, Stefanie Ehrenberg, Theresa Schmidt, Philipp Ritt, Margret I. Moré, Ralf Bergmann, Domokos Mathe, Konstantin Zhernosekov
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Abstract

The coinfusion of amino acids with targeted radiopharmaceutical therapy aims to reduce renal toxicity. Unfortunately, this requires a prolonged, large-volume infusion and often results in side effects such as nausea, vomiting, and hyperkalemia. Sodium paraaminohippurate is a nontoxic compound that has historically been used to measure renal plasma flow. It is excreted by the kidneys via glomerular filtration and tubular secretion using organic anion transporters. Paraaminohippurate has a favorable safety profile at plasma concentrations that saturate the maximum transport capacity of tubular cells. Therefore, paraaminohippurate may potentially reduce the renal accumulation of small-molecule radiopharmaceuticals. Methods: Preclinical studies, including ex vivo biodistribution, SPECT/CT, and PET analyses, were performed in Wistar rats to evaluate how coinjection of a paraaminohippurate solution affects the renal uptake of various radiopharmaceuticals compared with coinjection of a NaCl or arginine–lysine solution. Results: Paraaminohippurate was well tolerated, with no toxicity observed. Accumulated activity measured in the renal cortex was significantly lower for the small-peptide radiopharmaceuticals (0.9–2.5 kDa)—[177Lu]Lu-DOTATOC, [177Lu]Lu-DOTATATE, [177Lu]Lu-DOTA-JR11, [177Lu]Lu-DOTA-sargastrin, and [177Lu]Lu-DOTARGD—when paraaminohippurate was coinjected instead of NaCl. The renal uptake of [177Lu]Lu-DOTATOC, [177Lu]Lu-DOTATATE, and [177Lu]Lu-DOTA-JR11 was reduced by 46%, 83%, and 63%, respectively, at 1 h after injection with paraaminohippurate coinjection from the uptake after injection with NaCl. Kidney area-under-the-curve values were reduced by up to 60%, depending on the compound used. To a lesser extent, paraaminohippurate-mediated nephroprotection was observed with the prostate-specific membrane antigen (PSMA)–targeting molecules [177Lu]Lu-PSMA-I&T and [68Ga]Ga-PSMA-11. The renal uptake of the larger recombinant protein [177Lu]Lu-DOTA-Affiline-22 (18 kDa) and the folate derivative [99mTc]Tc-etarfolatide was not affected. These in vivo imaging data were confirmed by ex vivo biodistribution studies. Conclusion: Coinjection of paraaminohippurate at a high concentration was found to significantly reduce the renal uptake of a select number of small-molecule radiopharmaceuticals. This indicates the importance of tubular secretion, as well as the potential role of anion transporters that may be saturated by a high paraaminohippurate plasma concentration. Therefore, paraaminohippurate comedication could serve as a fast, safe, and convenient alternative to amino acid infusion as a nephroprotective agent during targeted radiopharmaceutical therapy.

在大鼠模型中,与对氨基马粪酸钠共给药减少各种放射性药物的肾脏摄取
氨基酸与靶向放射性药物治疗的联合输注旨在减少肾毒性。不幸的是,这需要长时间、大剂量的输注,并经常导致恶心、呕吐和高钾血症等副作用。对氨基马鞭酸钠是一种无毒化合物,历来用于测量肾血浆流量。它通过肾小球滤过和肾小管分泌通过有机阴离子转运体排出。对氨基马嘌呤具有良好的安全性,其血浆浓度可使小管细胞的最大运输能力饱和。因此,对氨基马粪酸可能潜在地减少小分子放射性药物的肾脏积聚。方法:临床前研究,包括体外生物分布、SPECT/CT和PET分析,在Wistar大鼠中进行,以评估与共注射NaCl或精氨酸-赖氨酸溶液相比,共注射副氨基马嘌呤溶液如何影响肾脏对各种放射性药物的摄取。结果:对氨基马粪酸耐受性良好,无毒性。小肽放射性药物(0.9-2.5 kDa) - [177Lu]Lu-DOTATOC、[177Lu]Lu-DOTATATE、[177Lu]Lu-DOTA-JR11、[177Lu]Lu-DOTA-sargastrin和[177Lu] lu - dotargd -当副胺马嘌呤代替NaCl共注射时,肾皮质累积活性显著降低。[177Lu]Lu-DOTATOC、[177Lu]Lu-DOTATATE和[177Lu]Lu-DOTA-JR11在注射副胺马嘌呤后1 h的肾脏摄取比注射NaCl后分别减少46%、83%和63%。肾脏曲线下面积值减少了60%,这取决于所使用的化合物。在较小程度上,通过前列腺特异性膜抗原(PSMA)靶向分子[177Lu]Lu-PSMA-I&;T和[68Ga]Ga-PSMA-11,观察到对氨基马嘌呤介导的肾保护作用。较大的重组蛋白[177Lu]Lu-DOTA-Affiline-22 (18 kDa)和叶酸衍生物[99mTc]Tc-etarfolatide的肾脏摄取不受影响。这些体内成像数据被体外生物分布研究证实。结论:联合注射高浓度对氨基马嘌呤可显著降低肾对部分小分子放射性药物的摄取。这表明小管分泌的重要性,以及阴离子转运体的潜在作用,阴离子转运体可能被高副胺嘌呤血浆浓度饱和。因此,在放射药物靶向治疗中,对氨嘌呤可作为一种快速、安全、方便的替代氨基酸输注的肾保护药物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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