Abstract
The effects of bovine serum albumin (BSA) and human serum albumin (HSA) on the unbound hepatic uptake clearance (PSu,inf) of the organic anion transporting polypeptide (Oatp/OATP) substrates 1-anilino-8-naphthalene sulfonate (ANS) and pitavastatin (PTV) were determined using primary cultured hepatocytes of rat and isolated hepatocytes of human, respectively. The PSu,inf value of hepatocytes was estimated by dividing the initial uptake rate of these anions by their unbound concentrations. The PSu,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)]. The model was able to describe accurately the relationship between the enhancement of the PSu,inf values and the albumin concentration. By considering the enhancement of hepatic uptake clearance by albumin, we could predict accurately the PSu,inf in vivo from that obtained in isolated hepatocytes using this "facilitated-dissociation" model. 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.
- in vitro-in vivo prediction (IVIVE)
- liver physiology/models
- liver/hepatic
- membrane permeability
- pharmacokinetics
- physiologically-based pharmacokinetic modeling/PBPK
- Uptake transporters (OATP, OAT, OCT, PEPT, MCT, NTCP, ASBT, etc.)
- The American Society for Pharmacology and Experimental Therapeutics