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

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.