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Tumour, whole-blood, plasma and tissue concentrations of metformin in lung cancer patients - PubMed

. 2023 Mar;89(3):1027-1035.

doi: 10.1111/bcp.15546. Epub 2022 Oct 12.

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Tumour, whole-blood, plasma and tissue concentrations of metformin in lung cancer patients

Joseph D Phillips et al. Br J Clin Pharmacol. 2023 Mar.

Abstract

Aim: Metformin is used for the management of type 2 diabetes mellitus (T2DM) and is being tested clinically as an anticancer agent. Metformin concentrations safely achievable in human solid tissues including tumours are unknown. This study was designed to determine metformin concentration in tissue compartments as a function of dose to inform rational dosing in preclinical models and interpretation of clinical results."

Methods: Subjects with solid tumours to be treated by resection and either (A) willingness to take metformin for 7-10 days before surgery or (B) taking metformin for T2DM were eligible. Whole blood, plasma, tumour, tumour-adjacent uninvolved tissue and subcutaneous adipose tissue were obtained for liquid chromatography with tandem mass spectrometry to measure metformin concentrations.

Results: All subjects had primary lung tumours. Metformin dose was significantly correlated with drug concentrations in all tissues analysed. Intersubject metformin concentrations varied by over two orders of magnitude. Metformin concentrations were significantly higher in tumour tissues and lower in adipose tissues compared to other tissues. Concentrations in blood and plasma were significantly correlated with concentrations in solid tissues.

Conclusion: Metformin accumulates in cellular compartments. Concentrations observed in plasma, blood, lung and tumour tissues in subjects treated with US Food and Drug Administration-approved doses for T2DM are lower than those typically used in tissue culture studies. However, such tissue concentrations are in line with those found within cultured cells treated with supra-pharmacological doses of metformin. Given the large intersubject variability in metformin concentrations, it is imperative to determine whether there is an association between tissue metformin concentration and anticancer activity in humans.

Keywords: cancer; metformin; tissue distribution.

© 2022 British Pharmacological Society.

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Conflict of interest statement

Conflicts of interest: LDL is a consultant to G1 Therapeutics and 7 Hills Pharma LLC and has received clinical trial support from Bristol Myers Squibb, AbbVie, Bayer Pharmaceuticals, and AstraZeneca.

Figures

Fig. 1-
Fig. 1-. Daily dose of metformin correlates with tissue concentrations.

Concentrations of metformin in plasma, blood, adipose, lung tissue, and tumor tissue available from 12, 14, 7, 12, and 11 subjects were compared to daily dose. Correlation testing included all replicates with metformin concentrations ≥LLOQ. Regression lines (thick) are plotted ± standard error of prediction by regression (thin). p-value of slopes were determined by t-test compared to the null hypothesis.

Fig. 2-
Fig. 2-. A linear mixed-effects model predicts metformin concentration by dose.

A linear mixed-effects model was applied accounting for inter-subject variation to predict tissue metformin concentration compared to daily dose. Lines are numbered according to tissue site in key.

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