Drug design based on the substrate specificity of the efflux transporters expressed in the blood-brain barrier

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1. The contribution of efflux transporter expressed in the blood-brain barrier was investigated in this study to identify the transporter which plays a major role in the detoxification system in the central nervous system. According to the comparison of efflux transport rate of estradiol 17β glucuronide after microinjection to the cerebral cortex in Mrp1 knockout mice and its wild-type suggested that Mrp1 plays a major role in the efflux transport of estradiol 17β glucuronide across the blood-brain barrier. In addition, it was turned out that multispecific organic anion transporters such as Oat3 and Oatp3 were expressed in the brain capillary where they localized on the abluminal membrane. In the blood CSF barreir, Oat3 and Oatp3 have been identified on the brush border membrane of the choroid epithelial cells, and they are responsible for the uptake of hydrophilic and amphipathic organic anions, respectively. Characterization of the uptake of cefaclor, a beta-lactam antibiotic reveale … More d the presence of additional uptake mechanism in the choroid plexus. These organic anion transporters provide barrier function to the brain capillary and choroid plexus, and keep the brain concentration of xenobiotics including drugs relatively low compared to their blood concentration. Especially for drugs, these transporters prevent CNS drugs reaching clinically significant concentrations in the brain by extruding drugs into the blood circulation. In addition to the drug transporters, we succeeded in characterization of Oatp14 as candidate transporter for thyroxine (T4). It is hypothesized that it plays an important role in supplying blood T4 into the central nervous system.2. The binding conformations of ligands of rat Oat3 by the automated conformational analysis program using molecular dynamics (CAMDAS) and the molecular superposing program based on the physical properties of functional groups in a molecular (SUPERPOSE) in order to search for the factors of substrate specificity of rat Oat3 in relation to three-dimensional structures of ligands. Finally, one binding conformation of ligands for Oat3 was obtained. Although Oat3 has broad substrate specificity, the substrate recognition by Oat3 can be described by one model. Less