Comparative Assessment of Extrapolation Methods Based on the Conventional Free Drug Hypothesis and Plasma Protein-Mediated Hepatic Uptake Theory for the Hepatic Clearance Predictions of Two Drugs Extensively Bound to Both the Albumin And Alpha-1-Acid Glycoprotein

Abstract

Bteich and coworkers recently demonstrated in a companion manuscript (J Pharm Sci 109: https://doi.org/10.1016/j.xphs.2020.07.003) that a protein-mediated hepatic uptake have occurred in an isolated perfused rat liver (IPRL) model for two drugs (Perampanel; PER and Fluoxetine; FLU) that bind extensively to the albumin (ALB) and alpha-1-acid glycoprotein (AGP). However, to our knowledge, there is no quantitative model available to predict the impact of a plasma protein-mediated hepatic uptake on the extent of hepatic clearance (CLh) for a drug binding extensively to these two proteins. Therefore, the main objective was to predict the corresponding CLh, which is an extension of the companion manuscript. The method consisted of extrapolating the intrinsic clearance from the unbound fraction measured in the perfusate or the unbound fraction extrapolated to the surface of the hepatocyte membrane by adapting an existing model of protein-mediated hepatic uptake (i.e., the fu_p-adjusted model) to include a binding ratio between the ALB and AGP. This new approach showed a relevant improvement compared to the free drug hypothesis particularly for FLU that showed the highest degree of ALB-mediated uptake. Overall, this study is a first step towards the development of predictive methods of CLh by considering the binding to ALB and AGP.