Since OCT1 and OCT3 are expressed in the plasma membrane of human hepatocytes, skeletal muscle cells, and adipocytes, an inhibition potential of OCT function by PPIs may abolish the glucose-lowering effect of metformin. Human adipocytes or human skeletal muscle cells is significantly reduced by known OCT inhibitors such as quinidine or cimetidine. Similarly, the activating effect of metformin on AMP-activated protein kinase is altered. Moreover, certain genotypes may directly affect the inhibition potential of a drug, a mechanism which is increasingly recognized. OCT1 pharmacogenetics and drug-drug interaction for metformin uptake and selected OCT1 inhibitors have recently been reported by in vitro experiments. Interestingly, an increased sensitivity to drug inhibition was observed for OCT variants, particularly for those with reduced function. While the glucose-lowering effect of metformin is LY2109761 impaired either in healthy volunteers or in diabetic Z-VAD-FMK 187389-52-2 patients carrying OCT1 variants with reduced function, no data are currently available with respect to PPI co-medication. Since generally only 60% of metformin-treated patients with type 2 diabetes do respond well, it might be possible that, clinically, PPIs are a yet unrecognized factor for insufficient metformin response due to a transporter-mediated drug-drug interaction via OCT transport proteins. Taken together, we identified PPIs as an important drug class inhibiting OCT-mediated metformin transport. Moreover, our present work underscores the impact of in silico pharmacophore modeling since these computational data have been confirmed by our experimental studies using transfected cell lines, which express functionally active OCTs. Additionally, this newly recognized in vitro drug-drug interaction warrants further clinical studies to elucidate the in vivo relevance in metformin-treated patients regarding drug disposition and/or pharmacodynamic consequences. The unchecked proliferation and invasion typical of cancer cells are processes that can only be sustained when there is sufficient energy supply, a feature that indicates the occurrence in transformed cells of distinct phenotypes that necessarily involve elements of the intermediary metabolism. In solid tumors it has been shown by Otto Warburg that cells have adapted to rely on anaerobic glycolysis as a strategy to maintain their prevailing anabolic status. However, the upregulation of glycolysis exhibited by cancer cells does not necessarily imply a strict anaerobic phenotype nor a dysfunctional oxidative phosphorylation system. Rather, it is believed that the normal interplay between the glycolysis in the cytosol and OXPHOS in the mitochondria becomes disturbed or reprogrammed in tumor cells. The Crabtree effect observed in cancer cells, or in rapidly proliferating cells exemplifies the intimate connection between glycolysis and the oxidative metabolism. Interestingly, the anaerobic phenotype exhibited by cancer cells may in fact represent the cause rather than the consequence of the adaptive pressure. By considering that the glycolytic switch typical of cancer cells is acquired at the very onset of carcinogenesis, the idea arose that alterations in the glycolytic pathway may predispose cells to malignant transformation. Selective advantages for the transformed cells could result from various features. For instance, it is known that hypoxia-inducible factor-1 greatly stimulates the expression of glucose and monocarboxylate transporters, glycolytic enzymes and induces a down regulation in pyruvate dehydrogenase complex.