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 MDR1a, 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 [3H]daunorubicin, [3H]digoxin, and [mebmt‐β‐3H]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.