The Phenomenon of Albumin-Mediated Hepatic Uptake of Organic Anion Transport Polypeptide Substrates: Prediction of the In Vivo Uptake Clearance from the In Vitro Uptake by Isolated Hepatocytes Using a Facilitated-Dissociation Model

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.