Transporters Involved in Metformin Pharmacokinetics and Treatment Response

Abstract

Metformin, widely used as first-line treatment for type 2 diabetes, exists primarily as a hydrophilic cation at physiological pHs. As such, membrane transporters play a substantial role in its absorption, tissues distribution, and renal elimination. Multiple organic cation transporters are determinants of the pharmacokinetics of metformin, and many of them are important in its pharmacological action, as mediators of metformin entry into target tissues. Further, a recent genomewide association study (GWAS) in a large multi-ethnic population implicated polymorphisms in SLC2A2, encoding the glucose transporter, GLUT2, as important determinants of response to metformin. Here, we describe the key transporters associated with metformin pharmacokinetics and response.

The effects of metformin on gut microbiota and the immune system as research frontiers

“…The effects of metformin on the microbiome and immune system may be relevant not only to diabetes treatment, but also to proposed novel indications, for example in oncology and ageing [51][52][53]. In future work, careful attention to whole organism and cellular pharmacokinetics [14] will be crucial to establishing the clinical relevance of laboratory studies.…”

“…Pharmacokinetic factors, as well as differences between cell lineages in the expression of the cell surface transporters that import the drug, imply that the drug accumulates in a heterogeneous manner between organs following oral administration [14]. The liver is a classic site of action of metformin and it is probably exposed to a higher level of the drug than other organs, following oral administration, because the portal circulation would be expected to have a higher drug concentration than the systemic circulation.…”

Mitochondrial targets of metformin—Are they physiologically relevant?

“…Other transporters from SLC22 and SLC47 families, for example, organic cation transporters (OCT1‐3) or carnitine/organic cation transporter (OCTN1), which are expressed in intestine were also proposed to be involved in metformin uptake . In addition, OCTs have also been implicated to play important role in metformin distribution in cancer cells and other tissues like liver or kidney . High expression of OCTs explains profound metformin accumulation in mouse liver (~40 μmol/L) when compared to serum (~5 μmol/L) …”

“…In conclusion, when interpreting identified molecular targets, one should use great caution regarding metformin doses used in any particular study. Furthermore, numerous confounding factors, such as subject's ethnicity, genetic background, mode of administration or even the analytical method used for estimation of metformin concentration can influence reported plasma levels …”

“…21 In addition, OCTs have also been implicated to play important role in metformin distribution in cancer cells 22 and other tissues like liver or kidney. 21 High expression of OCTs explains profound metformin accumulation in mouse liver (~40 μmol/L) when compared to serum (~5 μmol/L). 23 Metformin gastrointestinal absorption is imperfect and the plasma concentration fluctuates around 0.5-2 μg/mL (i.e., 4-15 μmol/L) in subjects taking 1.5-2.5 g of metformin orally per day (~30 mg kg −1 day −1 ).…”