Abstract

The effects of bovine serum albumin and human serum albumin on the unbound hepatic uptake clearance (PS_u,inf) of the organic anion–transporting polypeptide substrates 1-anilino-8-naphthalene sulfonate (ANS) and pitavastatin (PTV) were determined using primary cultured rat hepatocytes and isolated human hepatocytes, respectively. The PS_u,inf value of hepatocytes was estimated by dividing the initial uptake rate of these anions by their unbound concentrations. The PS_u,inf values for ANS and PTV were enhanced in the presence of albumin, thereby demonstrating the phenomenon of “albumin-mediated” hepatic uptake. We previously constructed a “facilitated-dissociation” model, in which the interaction of the ligand-albumin complex with the cell surface enhanced the dissociation of that complex to provide unbound ligand for uptake to the hepatocytes [J Pharmacokinet Biopharm 16:165–181 (1988)]. That model was able to describe accurately the relationship between the enhancement of the PS_u,inf values and the albumin concentration. By considering the enhancement of hepatic uptake clearance by albumin using this facilitated-dissociation model, we could predict accurately the PS_u,inf in vivo from that obtained in isolated hepatocytes. In the light of these findings, we suggest that the facilitated-dissociation model is applicable to describing the phenomenon of albumin-mediated hepatic uptake via organic anion transporters and to evaluating hepatic uptake clearance in vivo.