Metformin (1,1-dimethylbiguanide) is an orally administered drug, used as an insulin sensitizer in the treatment of type II diabetes (Nesti & Natali, 2017). Liver is the main site of metformins positive effects: metformin indirectly inhibits gluconeogenesis in the liver and reduces the concentration of glucose in blood. Oral dosing induces stronger and longer response than intravenous administration, since the gastrointestinal tract is an important target for metformin, affecting also liver via nervous system (Foretz and Viollet, 2015; Yerevanian & Soukas, 2019). Metformin increases glucose uptake and anaerobic metabolism in the gut, leading to increased lactate concentration in the intestine and plasma. Metformin also increases GLP-1 plasma concentration and expression of GLP-1 receptors in the pancreas. Metformin does not affect hepatic uptake or oxidation of free fatty acids, or re-secretion in humans, as shown in a [11C]palmitate PET study (Gormsen et al., 2018). Metformin reduces absorption of bile acids in ileum, leading to increased bile acid pool within intestine; this may be one of the reasons for reduced blood cholesterol levels, and altered microbiome (McCreight et al., 2016). Metformin reduces blood pressure by increasing urinary Na+ excretion in the kidneys (Hashimoto et al., 2018).
Metformin is toxic to cancer cells, and toxicity increases in combination with radiation (Brown et al., 2019).
Metformin is a strong base and it is positively charged under physiological pH. Its uptake in the gut is mostly transporter-dependent, and saturable, affected by inhibitors and other substrates of the transporters. Metformin is a substrate (and competitive inhibitor) for several transporters, such as organic cation transporters (OCT1, OCT2, OCT3), plasma membrane monoamine transporter (PMAT), multidrug and toxin extrusion proteins (MATE1 and MATE2), serotonin transporter (SERT), choline transporter (CHT) (McCreight et al., 2016), OCTN1, and thiamine transporter THTR-2. Genetic polymorphism of transporter genes affect the pharmacokinetics and effects of metformin. OCT1 is expressed in the liver and gut. OCT2 is expressed mainly in the kidneys, and with MATE1 is responsible for the excretion of metformin into urine. OCT3 is expressed in most tissues including intestine, but is the most important of OCTs in the skeletal muscle and adipose tissue, and salivary glands. PMAT is found mainly in the central nervous system but also in the intestine. Metformin can pass the blood-brain barrier (Moreira, 2014). Serotonergic signalling and the role of SERT is important in the regulation of gastrointestinal physiology.
Metformin does not metabolize in humans or animals, and is excreted in the bile and urine. Renal excretion is the main elimination pathway, because of reuptake of metformin in the intestine. In experimental rodent models orally administrated metformin accumulates in the mucosa of the small intestine in concentrations up to 300 times higher than in plasma (Tucker et al., 1981; Wilcock and Bailey, 1994).
Effect of metformin on PET studies
Since metformin is an inhibitor of several transporters, it may directly affect the distribution of some PET tracers. Inhibition of OCT1 and other transporters in the liver may reduce the rate of metabolism of PET tracers.
Metformin inhibits hexose-6-phosphate dehydrogenase in endoplasmic reticulum, which may lead to reduced [18F]FDG retention despite increased glycolytic flux (Marini et al., 2016).
Metformin increases the glucose uptake in the intestine (Koffert et al., 2017) and colon (Gontier et al., 2008); this leads to problems in diagnostic [18F]FDG PET studies of the abdominal area (McCreight et al., 2016). Variable effects of metformin on glucose uptake in tumours and other tissues may also cause bias in SUV estimates. Therefore metformin medication should be discontinued for at least 2 days before [18F]FDG PET scan.
[14C]Metformin has been to study pharmacokinetics of metformin in animal and cell models. [11C]Metformin has been used in PET studies for mice (Hume et al., 2013), pigs (Jakobsen et al., 2016), and humans (Gormsen et al., 2016). [11C]Metformin has may be a suitable PET radiopharmaceutical for quantifying the activities of the organic cation transporter 1 (OCT1) because OCT1 transports [11C]metformin from blood into the hepatocytes (Hume et al., 2013). In contrast to the previous expectations, the multidrug and toxin extrusion transporter 1 (MATE1) in the liver does not seem to transport [11C]metformin from hepatocytes into the bile, but into the blood; [11C]metformin is not excreted to the bile whether it is given orally or via intravenous injection (Gormsen et al., 2016). [11C]Metformin can also be used for quantification of renal clearance of metformin and the activity of OCT2 in kidney (Jakobsen et al., 2016).
Radioactive metabolites were not found in plasma or in urine (Gormsen et al., 2016).
Genetic polymorphism of transporter genes affect the pharmacokinetics and tissue uptake of metformin.
Tissue and plasma kinetics
After intravenous injection, most of [11C]metformin is cleared from the plasma after 20 min. Strongest uptake is seen in the kidneys, ureters, and bladder; marked accumulation was also seen in the liver, but not in the gallbladder; no uptake is seen in the brain and myocardium (Gormsen et al., 2016). [11C]Metformin tissue uptake is reversible, and reversible 2-tissue compartmental model fitted best the PET data from the liver (with both arterial and dual input), intestine, and skeletal muscle (though [11C]metformin concentration in skeletal muscle is only slightly higher than in plasma). Kidney TACs could not be fitted with compartmental model, but Logan plot can be used instead (Gormsen et al., 2016).
Erythrocyte membranes are known to contain at least OCTN1. In pharmacological doses metformin is slowly taken up by erythrocytes, and the elimination half-life from erythrocytes is 23 ± 2 h, nearly 10 times higher than that from plasma (Robert et al., 2003). In human PET studies the blood-to-plasma ratio was shown to be stable at 0.6 during the 90-min PET scan, suggesting that transport from plasma to erythrocytes is minimal even with tracer amount of labelled metformin.
Bryor R, Cabreiro F. Repurposing metformin: an old drug with new tricks in its binding pockets. Biochem J. 2015; 471: 307-322. doi: 10.1042/BJ20150497.
Chen L, Yee SW, Giacomini KM. OCT1 in hepatic steatosis and thiamine disposition. Cell Cycle 2015; 14(3): 283-284. doi: 10.1080/15384101.2015.1006532.
Gormsen LC, Sundelin EI, Jensen JB, Vendelbo MH, Jakobsen S, Munk OL, Christensen MMH, Brøsen K, Frøkiær J, Jessen N. In vivo imaging of human 11C-metformin in peripheral organs: dosimetry, biodistribution, and kinetic analyses. J Nucl Med. 2016; 57(12): 1920-1926. doi: 10.2967/jnumed.116.177774.
Hume WE, Shingaki T, Takashima T, Hashizume Y, Okauchi T, Katayama Y, Hayashinaka E, Wada Y, Kusuhara H, Sugiyama Y, Watanabe Y. The synthesis and biodistribution of [11C]metformin as a PET probe to study hepatobiliary transport mediated by the multi-drug and toxin extrusion transporter 1 (MATE1) in vivo. Bioorg Med Chem. 2013; 21: 7584-7590. doi: 10.1016/j.bmc.2013.10.041.
Hur KY, Lee MS. New mechanisms of metformin action: Focusing on mitochondria and the gut. J Diabetes Investig. 2015; 6(6): 600-609. doi: 10.1111/jdi.12328.
Jakobsen S, Busk M, Jensen JB, Munk OL, Zois NE, Alstrup AKO, Frøkiær J. A PET tracer for renal organic cation transporters, 11C-metformin: radiosynthesis and preclinical proof-of-concept studies. J Nucl Med. 2016; 57(4): 615-621. doi: 10.2967/jnumed.115.169292.
Koffert JP, Mikkola K, Virtanen KA, Andersson A-MD, Faxius L, Hällsten K, Heglind M, Guiducci L, Pham T, Silvola JMU, Virta J, Eriksson O, Kauhanen SP, Saraste A, Enerbäck S, Iozzo P, Parkkola R, Gomez MF, Nuutila P. Metformin treatment significantly enhances intestinal glucose uptake in patients with type 2 diabetes: results from a randomized clinical trial. Diabetes Res Clin Practice 2017; 131: 208-216. doi: 10.1016/j.diabres.2017.07.015.
McCreight LJ, Bailey CJ, Pearson ER. Metformin and the gastrointestinal tract. Diabetologia 2016; 59: 426-435. doi: 10.1007/s00125-015-3844-9.
Nesti L, Natali A. Metformin effects on the heart and the cardiovascular system: A review of experimental and clinical data. Nutr Metab Cardiovasc Dis. 2017; 27(8): 657-669. doi: 10.1016/j.numecd.2017.04.009.
Robert F, Fendri S, Hary L, Lacroix C, Andréjak M, Lalau JD. Kinetics of plasma and erythrocyte metformin after acute administration in healthy subjects. Diabetes Metab. 2003; 29(3): 279-283. PMID: 12909816.
Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F. Cellular and molecular mechanisms of metformin: an overview. Clin Sci. 2012; 122: 253-270. doi: 10.1042/CS20110386.
Updated at: 2019-04-30
Created at: 2016-02-02
Written by: Vesa Oikonen