Abstract

Background and Purpose

P-glycoprotein (P-gp) exhibits a broad specificity for substrates and affects their pharmacokinetics, especially intestinal absorption. However, it is challenging to predict in vivo P-gp mediated drug-drug interaction (DDI) and nonlinear absorption in the pre-clinical stage. The purpose of this study is to evaluate the use of hMDR1-MAC mice carrying human P-gp and lacking their own murine P-gp to quantitatively predict human P-gp mediated DDI and nonlinear absorption.

Experimental Approach

The P-gp substrates (aliskiren, betrixaban, celiprolol, digoxin, fexofenadine, and talinolol) were administered orally to wild-type, Mdr1a/b-KO, and hMDR1-MAC mice and their plasma concentrations were measured. We calculated the ratio of AUC (AUCR) in mice (AUC_Mdr1a/b-KO/AUC_wild-type or AUC_Mdr1a/b-KO/AUC_hMDR1-MAC) estimated as attributable to complete P-gp inhibition and the human AUCR with and without P-gp inhibitor administration. The correlations of AUCR_human with AUCR_wild-type and AUCR_hMDR1-MAC were investigated. For aliskiren, betrixaban, and celiprolol, the K_m and V_max values for P-gp in hMDR1-MAC mice and humans were optimized from different dosing studies using GastroPlus. The correlations of K_m and V_max for P-gp between human and hMDR1-MAC mice were investigated.

Key Results

A better correlation between AUCR_human and AUCR_hMDR1-MAC (R² = 0.88) was observed. Moreover, good relationships of K_m (R² = 1.00) and V_max (R² = 0.98) for P-gp between humans and hMDR1-MAC mice were observed.

Conclusions and Implications

These results suggest that P-gp mediated DDI and nonlinear absorption can be predicted using hMDR1-MAC mice. These mice are a useful in vivo tool for quantitatively predicting P-gp mediated disposition in drug discovery and development.