Species differences of inhibitory effects on P-glycoprotein-mediated drug transport

Previously, we clarified the species differences in P-glycoprotein (P-gp)mediated drug transport activity using human MDR1, monkey MDR1, canine MDR1, rat MD1 rat MDR1b, mouse mdr1a, and mouse mdr1b transfected LLC-PK1 cell lines. However, the species differences in the inhibitory effects on P-gp-mediated drug transport have not been clarified yet. The purpose of the present study was to evaluate the species differences in the inhibitory effects of typical P-gp inhibitors, quinidine and verapamil, on P-gp-mediated drug transport using MDR1 transfected cell lines. The transcellular transport of [H-3]daunorubicin, [H-3]digoxin, and [mebmt-beta-H-3]cyclosporin A across monolayers of the MDR1 transfected cells were measured in the presence or absence of P-gp inhibitors. On daunorubicin transport, the relative IC50 value (quinidine IC50/verapamil IC50) of human P-gp was 5.25 and those from other species ranged from 0.89 to 10.70. The transport of digoxin and cyclosporin A also showed different relative IC50 values among human, monkey, canine, rat, and mouse P-gps. The present study revealed that species differences in the inhibitory effects on P-gp-mediated drug transport should not be disregarded among human, monkey, canine, rat, and mouse. This study will provide useful information for predicting drug interactions mediated by P-gp. (C) 2006 Wiley-Liss, Inc.