Extrapolation of In Vivo Hepatic Clearance from In Vitro Uptake Clearance by Suspended Human Hepatocytes for Anionic Drugs with High Binding to Human Albumin: Improvement of In Vitro-to-In Vivo Extrapolation by Considering the “Albumin-Mediated” Hepatic Uptake Mechanism on the Basis of the “Facilitated-Dissociation Model”

• DOI: 10.1124/dmd.118.083733
• Publication Date: 2018-11-30T19:25:12Z
• Authors: Soo-Jin Kim; Kyeong-Ryoon Lee; Seiji Miyauchi; Yuichi Sugiyama
• Keywords: Human serum albumin; Serum Albumin; Dissociation constant

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