Metformin Reduces Renal Uptake of Radiotracers and Protects Kidneys from Radiation-Induced Damage

Abstract

Metformin is the most widely prescribed drug for type 2 diabetes. Chemically, metformin is a hydrophilic base that functions as an organic cation, suggesting that it may have the capacity to inhibit the tubular reabsorption of peptide radiotracers. The purpose of this study was to investigate whether metformin could reduce renal uptake of peptidyl radiotracers and serve as a radioprotective agent for peptide receptor radionuclide therapy (PRRT). We used two radiolabeled peptides: a 68 Ga-labeled cyclic (TNYL-RAW) peptide ( 68 Ga-NOTA-c(TNYL-RAW) (NOTA: 1,4,7 triazacyclononane-1,4,7-trisacetic acid) targeting EphB4 receptors and an 111 In- or 64 Cu-labeled octreotide ( 111 In/ 64 Cu-DOTA-octreotide) (DOTA: 1,4,7,10 triazacyclododecane-1,4,7,10-tetraacetic acid) targeting somatostatin receptors. Each radiotracer was injected intravenously into normal Swiss mice or tumor-bearing nude mice in the presence or absence of metformin administered intravenously or orally. Micro–positron emission tomography or micro–single-photon emission computed tomography images were acquired at different times after radiotracer injection, and biodistribution studies were performed at the end of the imaging session. To assess the radioprotective effect of metformin on the kidneys, normal Swiss mice received two doses of 111 In-DOTA-octreotide in the presence or absence of metformin, and renal function was analyzed via blood chemistry and histology. Intravenous injection of metformin with 68 Ga-NOTA-c(TNYL-RAW) or 111 In-DOTA-octreotide reduced the renal uptake of the radiotracer by 60% and 35%, respectively, compared to uptake without metformin. These reductions were accompanied by greater uptake in the tumors for both radiolabeled peptides. Moreover, the renal uptake of 111 In-DOTA-octreotide was significantly reduced when metformin was administered via oral gavage. Significantly more radioactivity was recovered in the urine collected over a period of 24 h after intravenous injection of 64 Cu-DOTA-octreotide in mice that received oral metformin than in mice that received vehicle. Finally, co-administration of 111 In-DOTA-octreotide with metformin mitigated radio-nephrotoxicity. Metformin inhibits kidney uptake of peptidyl radiotracers, protecting the kidney from nephrotoxicity. Further studies are needed to elucidate the mechanisms of these finding and to optimize mitigation of radiation-induced damage to kidney in PRRT.