A transcellular assay to assess the P-gp inhibition in early stage of drug development.

To provide a fast assessment in predicting P-gp-mediated DDI risk during early stage of drug development, a transcellular P-gp inhibition assay using two concentrations is presented in the present study. The efflux ratios of loperamide in the presence of forty-five commercial compounds at two concentrations were measured and compared to that of six concentrations in human P-gp cDNA-expressing LLC-PK1 cells (LLC-MDR1). The inhibition potency calculated from the change on the efflux ratio (ER) and on the net secretory flux (NSF) of loperamide was investigated. The P-gp inhibition potency was defined as potent (IC50 < 1 µM), moderate (1 µM < IC50 < 10 µM), or weak (IC50 > 10 µM). The results using 1 µM and 10 µM of inhibitor concentrations provided the best correlation and are most consistent with those generated from a 6-point approach.