Marian Meckel, Stefanie Ehrenberg, Theresa Schmidt, Philipp Ritt, Margret I. Moré, Ralf Bergmann, Domokos Mathe, Konstantin Zhernosekov
{"title":"Reduced Renal Uptake of Various Radiopharmaceuticals with Sodium Paraaminohippurate Coadministration in a Rat Model","authors":"Marian Meckel, Stefanie Ehrenberg, Theresa Schmidt, Philipp Ritt, Margret I. Moré, Ralf Bergmann, Domokos Mathe, Konstantin Zhernosekov","doi":"10.2967/jnumed.124.268411","DOIUrl":null,"url":null,"abstract":"<p>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. <strong>Methods:</strong> 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. <strong>Results:</strong> 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)—[<sup>177</sup>Lu]Lu-DOTATOC, [<sup>177</sup>Lu]Lu-DOTATATE, [<sup>177</sup>Lu]Lu-DOTA-JR11, [<sup>177</sup>Lu]Lu-DOTA-sargastrin, and [<sup>177</sup>Lu]Lu-DOTARGD—when paraaminohippurate was coinjected instead of NaCl. The renal uptake of [<sup>177</sup>Lu]Lu-DOTATOC, [<sup>177</sup>Lu]Lu-DOTATATE, and [<sup>177</sup>Lu]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 [<sup>177</sup>Lu]Lu-PSMA-I&T and [<sup>68</sup>Ga]Ga-PSMA-11. The renal uptake of the larger recombinant protein [<sup>177</sup>Lu]Lu-DOTA-Affiline-22 (18 kDa) and the folate derivative [<sup>99m</sup>Tc]Tc-etarfolatide was not affected. These in vivo imaging data were confirmed by ex vivo biodistribution studies. <strong>Conclusion:</strong> 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.</p>","PeriodicalId":22820,"journal":{"name":"The Journal of Nuclear Medicine","volume":"43 1","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"The Journal of Nuclear Medicine","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.2967/jnumed.124.268411","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
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.