A Novel Experimental and Theoretical Method for Estimating Albumin-Mediated Hepatic Uptake Based on the Albumin Binding Fraction in Plasma and Human PK Prediction Using a Physiologically-Based Pharmacokinetic Approach.

ABSTRACT

Recently, protein-facilitated uptake has been suggested to be an important factor in the precise prediction of the pharmacokinetic (PK) profiles of drugs. In our previous study, a physiologically-based pharmacokinetic (PBPK) approach considering the mechanism of albumin-mediated hepatic uptake was developed for predicting human PK profiles. It was assumed that drugs affected by albumin-mediated hepatic uptake would bind only to albumin, which means that there would be over-estimation of the contribution of protein-facilitated uptake for a drug that could bind to multiple proteins. In this study, we developed a method that can evaluate the albumin binding fraction in plasma considering the affinity for other proteins. Based on the albumin binding fraction, the contribution of albumin-mediated hepatic uptake was theoretically estimated, and then the human PK profiles were predicted by our proposed PBPK approach incorporating this mechanism. As a result, the predicted human PK profiles agreed well with the observed ones, and the absolute average fold error of PK parameters was almost within a 1.5-fold error on average. These findings show the importance of considering protein-facilitated uptake and also suggest that our proposed PBPK approach can be useful in scientific discussions with regulatory authorities.