is excreted unchanged, primarily via kidney excretion. The plasma monoamine transporter Slc29a4, also known as Pmat, mediates the intestinal absorption of the drug. Slc22a3 and possibly Slc22a1 may also contribute to its uptake by enterocytes. Hepatic uptake is mediated primarily by Slc22a1 with possible contributions from Slc22a3. The major mediator of renal metformin uptake is Slc22a2. Slc22a1, Slc22a2 and Slc22a3 are also known as Oct1, Oct2 and Oct3 respectively and are members of the organic cation family of transporters - the solute carrier family, subfamily 22. Renal excretion of metformin is mediated by Slc47a1 and Slc47a2 with Slc47a1 possibly mediating hepatic excretion as well. As metformin transport is the main aspect of metformin pharmacokinetics, polymorphisms in these transporters can have a direct impact on the availability of and the responses to the drug. In addition, drug-drug interactions can also affect metformin transport. Proton-pump inhibitors inhibit metformin uptake in vitro, anti-diabetic drugs such as repaglinide can inhibit its transport in vivo. The antihyperglycemic effects of metformin are due to the activation of adenosine monophosphate-activated kinase (AMPK) signaling pathway. The mechanisms by which metformin activates AMPK are not well understood and there are reasons to believe that the AMPK cascade is not the primary target. AMPK is an energy sensor and fuel regulator - it promotes ATP-producing and inhibits ATP-consuming pathways. AMPK inhibits gluconeogenesis, cholesterol and fatty acid synthesis; it stimulates fatty acid oxidation and glucose uptake. AMPK also impacts on components of mTOR pathway to inhibit its signaling. However, neither AMPK nor its upstream activating Lkb1 complex are direct targets of the drug. The main target of metformin appears to be the mitochondrial respiratory chain - the electron transfer pathway, with the drug specifically inhibiting complex I. Like in the case of AMPK activation, the molecular mechanisms of inhibition of the respiratory chain are largely unknown. Metformin is the focus of intense current research for its potential role as an anti-cancer agent; reports indicate that cancer risk is reduced in diabetic patients. T2D is associated with an increased risk of cancer, in particular breast, colon, kidney, pancreas and prostate neoplasms and metformin reduces the relative risk of breast, prostate and pancreatic cancers. Metformin also exerts an inhibitory effect on the mitochondrial production of reactive oxygen species (ROS). The change in AMP:ATP ratio and the activation of AMPK, the inhibition of energy-consuming processes and of ROS generation can account for the tumor suppressing effects of this antihyperglycemic drug. The side effects of metformin administration are generally mild; the drug is a risk factor for lactic acidosis and can produce nausea and gastrointestinal (GI) disturbances. To see the ontology report for Gviewer, annotations and download, click here ...(less)