Mechanisms of Intestinal Absorption of Metformin

Mechanisms of Intestinal Absorption of Metformin

Metformin, a widely prescribed antihyperglycemic agent used in treating non-insulin dependent diabetes, has garnered a lot of interest from clinicians and pharmaceutical companies, due to its widespread prescriptions, high dose, and uncertainty regarding potential drug-drug interactions.  Metformin has high bioavailability and fraction of dose absorbed, which is surprising due to its hydrophilic and charged properties.  In addition, metformin has been shown in the clinic to have dose-dependent absorption, suggesting a saturable transport mechanism in its absorption.  Using Caco-2 intestinal cell model, saturable absorptive transport and cellular uptake of metformin has been demonstrated.  Using kinetic modeling techniques, it has been estimated that metformin, although a potential substrate for various organic cation transporters (OCTs), is transported across the Caco-2 cell monolayer predominantly via the paracellular route; yet its transport is saturable.  This observation is the most convincing evidence of a novel saturable transport mechanism in the paracellular space for a small cationic drug.  Future work will focus on elucidating this paracellular mechanism using modified cell models in order to tease out the tight junction proteins that are responsible for the saturable absorption.  In addition, preclinical and clinical in vivo studies will be designed to test the hypotheses generated regarding the absorptive mechanisms of metformin across intestinal epithelium using in vitro model systems.  Will Proctor is currently working on this project.  Previous contributors to the related project on the intestinal transport mechanisms of hydrophilic cations, such as ranitidine and famotidine, are: Kiho Lee, Ph.D. (1999),  Chee Ng, Ph.D. (2004),  and David Boudet (2005).