In Vivo Imaging of Human ¹¹C-Metformin in Peripheral Organs: Dosimetry, Biodistribution, and Kinetic Analyses

Abstract

Metformin is the most widely prescribed oral antiglycemic drug, with few adverse effects. However, surprisingly little is known about its human biodistribution and target tissue metabolism. In animal experiments, we have shown that metformin can be labeled by 11 C and that 11 C-metformin PET can be used to measure renal function. Here, we extend these preclinical findings by a first-in-human 11 C-metformin PET dosimetry, biodistribution, and tissue kinetics study. Methods: Nine subjects (3 women and 6 men) participated in 2 studies: in the first study, human radiation dosimetry and biodistribution of 11 C-metformin were estimated in 4 subjects (2 women and 2 men) by whole-body PET. In the second study, 11 C-metformin tissue kinetics were measured in response to both intravenous and oral radiotracer administration. A dynamic PET scan with a field of view covering target tissues of metformin (liver, kidneys, intestines, and skeletal muscle) was obtained for 90 (intravenous) and 120 (oral) min. Results: Radiation dosimetry was acceptable, with effective doses of 9.5 mSv/MBq (intravenous administration) and 18

A Study on Pharmacokinetics of Bosentan with Systems Modeling, Part 1: Translating Systemic Plasma Concentration to Liver Exposure in Healthy Subjects

“…To address the challenge of understanding human liver exposure, positron emission tomography (PET) studies for transporter substrates have been developed (Shimizu et al, 2012;Gormsen et al, 2016). In addition to excessive cost and potential difficulties in labeling compounds, the usefulness of this approach is still limited to compounds with minimal metabolism.…”

Metformin does not compromise energy status in human skeletal muscle at rest or during acute exercise: A randomised, crossover trial

“…The metformin contents in the blood, with peak values of ~20–30 µM, are in the upper level compared to reported clinical values (Cusi & DeFronzo, ). Recently Gormsen et al (), using in vivo imaging of labeled 11 C‐metformin by PET, reported a low metformin uptake rate but accumulation over time. This is in line with our observation of increasing metformin muscle content in skeletal muscle over time, that is elevated in ST‐MES compared to A‐MES.…”

Direct assessment of renal mitochondrial redox state using hyperpolarized 13C‐acetoacetate

“…Numerous studies have shown that metformin specifically inhibits complex I (21), especially at high doses (22), resulting in an increased mitochondrial NADH/NAD þ ratio. The hepatic mitochondrion is widely considered to be the primary site of metformin action, but metformin also distributes extensively to kidney via related organic cation transporters (OCTs), especially when injected intravenously (23). To assess the sensitivity of HP bOHB production to changes in mitochondrial redox state, 4 of the 8 rats were scanned using HP [1,3-13 C 2 ]AcAc 45 min after acute high dose treatment with metformin (125 mg/kg, intravenous, dissolved in 1 mL phosphate buffered saline).…”