Jørgen Frøkiær

Metformin is the most widely prescribed oral anti-glycemic 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 labelled by (11)C and that (11)C-metformin Positron emission tomography (PET) can be used to measure renal function. Here, we extend these pre-clinical findings by a first-in-human (11)C-metformin PET dosimetry, biodistribution and tissue kinetics study.

METHODS: Nine subjects (three women, six men) participated in two studies: In the first study, human radiation dosimetry and biodistribution of (11)C-metformin were estimated in 4 subjects (two women and two 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 performed for 90 (intravenous) and 120 (oral) minutes.

RESULTS: Radiation dosimetry was acceptable with effective doses 9.5 (intravenous) and 18.1 μSv/MBq (oral) administrations. Whole body PET revealed, that (11)C-metformin was primarily taken up by the kidneys, urinary bladder and liver but also to a lesser extent in salivary glands, skeletal muscle and intestines. Reversible 2-tissue compartment kinetics was observed in the liver and volume of distribution (Vd) was calculated to be 2.45 ml/ml (arterial input) or 2.66 ml/ml (portal and arterial input). In the kidneys, compartmental models did not adequately fit the experimental data and Vd was therefore estimated by a linear approach to be 6.83 ml/ml. Skeletal muscle and intestinal tissue kinetics were best described by 2-tissue compartment kinetics and showed only discrete tracer uptake. Liver (11)C-metformin uptake was pronounced after oral administration of the tracer with tissue-to-blood ratio double what was observed after intravenous administration. Only slow accumulation of (11)C-metformin was observed in muscle. There was no elimination of (11)C-metformin through the bile both during the intravenous and the oral part of the study.

CONCLUSION: (11)C-metformin is suitable for imaging metformin uptake in target tissues and may prove a valuable tool to assess the impact of metformin treatment in patients with varying metformin transport capacity.