Predicting quantitatively P-glycoprotein mediated drug-drug interactions and intestinal absorption using humanized mice

Publication: Br J Pharmacol
Software: GastroPlus®


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 (AUCMdr1a/b-KO/AUCwild-type or AUCMdr1a/b-KO/AUChMDR1-MAC) estimated as attributable to complete P-gp inhibition and the human AUCR with and without P-gp inhibitor administration. The correlations of AUCRhuman with AUCRwild-type and AUCRhMDR1-MAC were investigated. For aliskiren, betrixaban, and celiprolol, the Km and Vmax values for P-gp in hMDR1-MAC mice and humans were optimized from different dosing studies using GastroPlus. The correlations of Km and Vmax for P-gp between human and hMDR1-MAC mice were investigated.

Key Results

A better correlation between AUCRhuman and AUCRhMDR1-MAC (R2 = 0.88) was observed. Moreover, good relationships of Km (R2 = 1.00) and Vmax (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.