Drug-drug interactions that occur at the level of drug transporters can have unexpected and severe side effects. The hepatic drug transporters of the organic anion transporting polypeptide (OATP) superfamily transport numerous endo- and xenobiotics (drugs) and are therefore important for drug disposition. The two liver specific OATP1B1 and OATP1B3 have broad and overlapping substrate specificity, but also transport distinct and unique substrates. However, there is nothing known about how OATPs recognize and transport different compounds. So far it is impossible to make exact predictions on whether a compound will be a substrate or not, and whether a possible drug-interaction might occur. Because OATPs are potential sites of drug-drug interactions that can lead to severe adverse effects, these unknowns should be clarified. Therefore, the long-term goal of the proposed studies is to understand, predict and prevent OATP related drug-drug interactions. The objective of this particular application is to determine the molecular basis of the polyspecificity of the liver-specific transporters, OATP1B1 and OATP1B3. The central hypothesis for the proposed research is that different substrates are transported by OATP1B1 and OATP1B3 using multiple transport/binding sites. Malfunction of these transporters (inhibition, up- or down-regulation, and polymorphisms) will affect drug bioavailability and can lead to adverse drug actions. We plan to test our central hypothesis and accomplish the overall objective of this application with the following four specific aims: 1) Characterize the substrate specificity of OATP1B1 and OATP1B3 with emphasis on nuclear receptor ligands; 2) Perform a detailed 3D-QSAR analysis for OATP1B1 and OATP1B3; 3) Determine the membrane topology; and 4) Identify the substrate binding sites of OATP1B1 and OATP1B3 using chimeras and site directed mutagenesis. A detailed understanding on how the liver specific drug transporters OATP1B1 and OATP1B3 recognize and transport their different substrates will help to predict and prevent adverse drug-drug interactions and to develop new therapeutic compounds to target the liver. Once this knowledge is available, there is the promise that it will be possible to develop safer medication which will result in less hospitalizations. ? ? ? ? ?
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