Figure 1. Systemic effects of biguanides.

Following oral administration, biguanides have local effects on the GI tract, including the colon, as the luminal concentration can exceed the serum concentration. This elevated concentration may explain observed antiproliferative effects of metformin on colon epithelial cells (92, 93). Absorbed drugs are initially routed to the liver via the portal circulation, and this organ is exposed to high concentrations relative to others, not only because it receives portal circulation, but also because hepatocytes express high levels of cell surface transport molecules such as OCT1 required for the import of biguanides such as metformin. In liver, gluconeogenesis is inhibited, leading to declines in circulating glucose and insulin, particularly in the setting of elevated baseline levels. A variety of actions may also occur in other organs, including potentially antiinflammatory actions (40), antiproliferative actions (21), prosurvival actions (83), and antiaging actions (22). However, these effects are dependent on adequate drug levels, and knowledge concerning organ-specific pharmacokinetics of metformin is incomplete.