Biodistribution and Elimination Study of Fluorine-18 Labeled Nε-Carboxymethyl-Lysine following Intragastric and Intravenous Administration

Abstract

BackgroundNε-carboxymethyl-lysine (CML) is a major advanced glycation end-product (AGEs) widely found in foods. The aim of our study was to evaluate how exogenous CML-peptide is dynamically absorbed from the gastrointestinal tract and eliminated by renal tubular secretion using microPET imaging.MethodsThe present study consisted of three investigations. In study I, we synthesized the imaging tracer 18F-CML by reacting N-succinimidyl 4-18F-fluorobenzoate (18F-SFB) with CML. In study II, the biological activity of 18F-CML was evaluated in RAW264.7 cells and HepG2 cells. In study III, the biodistribution and elimination of AGEs in ICR mice were studied in vivo following tail vein injection and intragastric administration of 18F-CML.ResultThe formation of 18F-CML was confirmed by comparing its retention time with the corresponding reference compound 19F-CML. The radiochemical purity (RCP) of 18F-CML was >95%, and it showed a stable character in vitro and in vivo. Uptake of 18F-CML by RAW264.7 cells and HepG2 cells could be inhibited by unmodified CML. 18F-CML was quickly distributed via the blood, and it was rapidly excreted through the kidneys 20 min after tail vein injection. However, 18F-CML was only slightly absorbed following intragastric administration. After administration of 18F-CML via a stomach tube, the radioactivity was completely localized in the stomach for the first 15 min. At 150 min post intragastric administration, intense accumulation of radioactivity in the intestines was still observed.ConclusionsPET technology is a powerful tool for the in vivo analysis of the gastrointestinal absorption of orally administered drugs. 18F-CML is hardly absorbed by the gastrointestinal tract. It is rapidly distributed and eliminated from blood following intravenous administration. Thus, it may not be harmful to healthy bodies. Our study showed the feasibility of noninvasively imaging 18F-labeled AGEs and was the first to describe CML-peptide gastrointestinal absorption by means of PET.

Quantitative assessment of organ distribution of dietary protein‐bound 13C‐labeled Nɛ‐carboxymethyllysine after a chronic oral exposure in mice

“…Previous studies have attempted to examine the metabolic fate of dCML either with a 14 C‐labeled CML or an 18 F‐labeled CML . The limitations of these studies detailed in the introduction section were the motivation for developing our new analytical method which can differentiate supplemented dCML accurately from nCML.…”

“…When the biodistribution of CML and other AGEs was studied after a dietary exposure, a dominant deposition in the kidneys was always observed compared to the few other tissues tested . It must be pointed out that some authors described only a temporary accumulation of dCML . The total amount of CML (i.e.…”

“…To assess the accumulation of dCML in tissues, a specific CML derivative was synthetized using fluorine‐18 ( 18 F) . Although the 18 F‐labeled CML was presented as a meaningful model for a CML dipeptide in vivo, it must be taken into account that the fluorobenzoylation of CML changes the chemical structure of CML.…”

“…The few studies which have followed the distribution of dCML in rodents’ bodies have administrated dCML either as a single free amino acid into the stomach by oral gavage or dCML bound to a nonphysiological dipeptide by intravenous injection . The methods of exposure to dCML employed in these animal studies, unfortunately, had biases which limited the possibility of comparison to human exposure.…”

Urinary excretion of dietary Maillard reaction products in healthy adult female cats1,2

“…When injected intravenously in the tail of rats, [ 18 F]fluorobenzoylated CML was found to accumulate quickly in the liver and kidneys and in lesser amounts in the muscles and heart. After 120 min, however, 72.3% of the radioactivity was found in the urine bladder, whereas 18.1% had accumulated in the kidneys and hardly any accumulation was reported in other organs (Xu et al, 2013). When administered via a stomach tube, most [ 18 F]fluorobenzoylated CML is still located in the stomach and intestines (17.9% and 48.3%) after 120 min, and 29.6% is found in the urine bladder.…”