ed in several tissues through the action of a number of transporters. The uptake and efflux of the drug are the major components of its pharmacokinetics profile as the drug is not metabolized and is excreted unchanged, primarily via kidney secretion. Metformin reduces the levels of glucose both in the basal state and post-prandial; the antihyperglycemic effects 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. However, the maximal effect of metformin is lower, approximately half the effect of rotenone - the standard complex I inhibitor that inhibits the transfer of electrons from the iron-sulfur centers to ubiquinone. Likely, the mode of action of the two drugs is different. The positive charge of the drug is proposed to account for its accumulation inside the energized mitochondrial matrix while its apolar side chain may promote its association with the mitochondrial membrane. Inhibition of complex I leads to lowering of the proton gradient and reduction of the proton-driven synthesis of ATP. The resulting change/increase in AMP:ATP ratio can contribute to the activation of AMP-responsive AMPK signaling. 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 respiratory complex I is the largest of the four complexes involved in the electron transfer pathway; the fifth complex uses the generated proton gradient for the synthesis of ATP. The simpler bacterial complex I whose 14 'core' subunits are highly conserved represents a model for the human mitochondrial complex; its structure from Thermus thermophilus has been solved. The additional 'accessory' subunits of the mammalian complex which totals some 44 components are thought to aid in the assembly, stability and/or regulation of the complex. Polymorphisms in a number of transporters impact on metformin drug pathway in addition to drug-drug interactions such as the inhibition of metformin transport by proton-pump inhibitors or the antidiabetic drug repaglinide. 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. Studies in rodents show that a very high dose of metformin has toxic effects....(less)