Quantitative Evaluation of mMate1 Function Based on Minimally Invasive Measurement of Tissue Concentration Using PET with [11C]Metformin in Mouse

Shingaki, Tomotaka; Hume, W. Ewan; Takashima, Tadayuki; Katayama, Yumiko; Okauchi, Takashi; Hayashinaka, Emi; Wada, Yasuhiro; Cui, Yilong; Kusuhara, Hiroyuki; Sugiyama, Yuichi; Watanabe, Yasuyoshi

doi:10.1007/s11095-015-1642-1

Cited by 26 publications

(38 citation statements)

References 34 publications

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“…Recent data show decreased antiglycemic effects of metformin in OCT3 2/2 mice (23), and our data could indicate a minor hepatic OCT3-mediated uptake of metformin. Inhibition of MATE1 with pyrimethamine did not affect hepatic uptake of metformin, consistent with a recent study by Shingaki et al (15). To further test the role of MATE1, we pretreated two OCT1/2 2/2 mice with pyrimethamine and determined metformin distribution.…”

Section: Discussionsupporting

confidence: 87%

“…11 C]-labeled metformin ([ 11 C]-metformin) was recently demonstrated to be a powerful tool to noninvasively determine distribution of metformin in specific tissues (14)(15)(16). Therefore, the primary aim of the present study was to use dynamic positron emission tomography (PET) with [ 11 C]-metformin in mice to investigate the importance of OCT and MATE in dynamic hepatic and small intestinal distribution of metformin in vivo.…”

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confidence: 99%

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[11C]-Labeled Metformin Distribution in the Liver and Small Intestine Using Dynamic Positron Emission Tomography in Mice Demonstrates Tissue-Specific Transporter Dependency

et al. 2016

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Metformin is the most commonly prescribed oral antidiabetic drug, with well-documented beneficial preventive effects on diabetic complications. Despite being in clinical use for almost 60 years, the underlying mechanisms for metformin action remain elusive. Organic cation transporters (OCT), including multidrug and toxin extrusion proteins (MATE), are essential for transport of metformin across membranes, but tissue-specific activity of these transporters in vivo is incompletely understood. Here, we use dynamic positron emission tomography with [11C]-labeled metformin ([11C]-metformin) in mice to investigate the role of OCT and MATE in a well-established target tissue, the liver, and a putative target of metformin, the small intestine. Ablation of OCT1 and OCT2 significantly reduced the distribution of metformin in the liver and small intestine. In contrast, inhibition of MATE1 with pyrimethamine caused accumulation of metformin in the liver but did not affect distribution in the small intestine. The demonstration of OCT-mediated transport into the small intestine provides evidence of direct effects of metformin in this tissue. OCT and MATE have important but separate roles in uptake and elimination of metformin in the liver, but this is not due to changes in biliary secretion. [11C]-Metformin holds great potential as a tool to determine the pharmacokinetic properties of metformin in clinical studies.

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Section: Discussionsupporting

confidence: 87%

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confidence: 99%

[11C]-Labeled Metformin Distribution in the Liver and Small Intestine Using Dynamic Positron Emission Tomography in Mice Demonstrates Tissue-Specific Transporter Dependency

et al. 2016

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“…However, in some tissues, metformin can accumulate at concentrations several-times higher than those found in the bloodstream [50], as demonstrated for the adrenal gland and liver [51]. The adrenal gland is in fact one of the tissues expressing the highest levels of the organic cation transporters 1 (Oct 1) and 3 (Oct 3) [52], which are responsible for metformin cellular uptake and for its high concentration in this organ [53].…”

Section: Discussionmentioning

confidence: 99%

Metformin as a new anti-cancer drug in adrenocortical carcinoma

et al. 2016

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Adrenocortical carcinoma (ACC) is a rare heterogeneous malignancy with poor prognosis. Since radical surgery is the only available treatment, more specific and effective drugs are urgently required. The anti-diabetic drug metformin has been associated with a decreased cancer prevalence and mortality in several solid tumors, prompting its possible use for ACC treatment.This paper evaluates the in vitro and in vivo anti-cancer effects of metformin using the ACC cell model H295R.Metformin treatment significantly reduces cell viability and proliferation in a dose- and time-dependent manner and associates with a significant inhibition of ERK1/2 and mTOR phosphorylation/activation, as well as with stimulation of AMPK activity. Metformin also triggers the apoptotic pathway, shown by the decreased expression of Bcl-2 and HSP27, HSP60 and HSP70, and enhanced membrane exposure of annexin V, resulting in activation of caspase-3 apoptotic effector. Metformin interferes with the proliferative autocrine loop of IGF2/IGF-1R, which supports adrenal cancer growth. Finally, in the ACC xenograft mouse model, obtained by subcutaneous injection of H295R cells, metformin intraperitoneal administration inhibits tumor growth, confirmed by the significant reduction of Ki67%.Our data suggest that metformin inhibits H295R cell growth both in vitro and in vivo. Further preclinical studies are necessary to validate the potential anti-cancer effect of metformin in patients affected by ACC.

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“…PET-labeled drugs have also been used to validate that pharmacokinetics and distribution from preclinical studies can be extended to humans (e.g., 11 C-donepezil) (5). However, 11 C-metformin has to our knowledge previously been used only in 2 small-animal studies (6,7).…”

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

et al. 2016

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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

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Quantitative Evaluation of mMate1 Function Based on Minimally Invasive Measurement of Tissue Concentration Using PET with [11C]Metformin in Mouse

Abstract: Tissue concentration based investigations using [(11)C]metformin by PET enables the functional analysis of MATEs in the liver and kidneys.

Cited by 26 publications

References 34 publications

[11C]-Labeled Metformin Distribution in the Liver and Small Intestine Using Dynamic Positron Emission Tomography in Mice Demonstrates Tissue-Specific Transporter Dependency

[11C]-Labeled Metformin Distribution in the Liver and Small Intestine Using Dynamic Positron Emission Tomography in Mice Demonstrates Tissue-Specific Transporter Dependency

Metformin as a new anti-cancer drug in adrenocortical carcinoma

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

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Quantitative Evaluation of mMate1 Function Based on Minimally Invasive Measurement of Tissue Concentration Using PET with [11C]Metformin in Mouse

Abstract: Tissue concentration based investigations using [(11)C]metformin by PET enables the functional analysis of MATEs in the liver and kidneys.

Cited by 26 publications

References 34 publications

[11C]-Labeled Metformin Distribution in the Liver and Small Intestine Using Dynamic Positron Emission Tomography in Mice Demonstrates Tissue-Specific Transporter Dependency

[11C]-Labeled Metformin Distribution in the Liver and Small Intestine Using Dynamic Positron Emission Tomography in Mice Demonstrates Tissue-Specific Transporter Dependency

Metformin as a new anti-cancer drug in adrenocortical carcinoma

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

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