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Extrapolation of In Vivo Hepatic Clearance from In Vitro Uptake Clearance by Suspended Human Hepatocytes (IVIVE) for Anionic Drugs with High Binding to Human Albumin: Improvement of IVIVE by Considering the "Albumin-Mediated" Hepatic Uptake Mechanism Based on the facilitated-dissociation Model.

We investigated whether human serum albumin (HSA) would affect the uptake clearance of anionic drugs with high binding to HSA by suspended human hepatocytes and improve the extrapolation of in vivo hepatic clearance from in vitro uptake clearance by the hepatocytes via the "albumin-mediated" hepatic uptake mechanism. The uptake clearances for total forms ( PS inf ) and for unbound forms ( PS u,inf ) of 11 anionic drugs (all of which were organic anion-transporting polypeptide (OATP) substrates) were determined with suspended human hepatocytes in varying concentrations of HSA. The fraction ( f u ) of unbound drugs was determined using an equilibrium dialysis at various HSA concentrations. The PS inf values decreased with increasing concentrations of HSA, whereas the unbound uptake clearances ( PS u,inf (+)= PS inf / f u ) in the presence of HSA were increased substantially, thus demonstrating the "albumin-mediated" hepatic uptake mechanism. The relationships between PS inf and HSA concentration were well described by the previously proposed facilitated-dissociation model in which the drug - albumin complex interacts with the cell surface, enhancing the dissociation of the complex and providing unbound drug for hepatic uptake. Furthermore, the PS u,inf (+) values in in vivo conditions (at 5% HSA) were predicted from those obtained in isolated hepatocytes based on the facilitated-dissociation model, revealing compatibility with the overall hepatic intrinsic clearance in vivo We conclude that the facilitated-dissociation model is useful to describe the "albumin-mediated" hepatic uptake phenomenon of OATP drugs and to predict hepatic uptake clearance in vivo .

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