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

✍ Scribed by Naoto Suzuyama; Miki Katoh; Toshiyuki Takeuchi; Sumie Yoshitomi; Tomoaki Higuchi; Satoru Asashi; Tsuyoshi Yokoi

• Publisher: John Wiley and Sons
• Year: 2007
• Tongue: English
• Weight: 277 KB
• Volume: 96
• Category: Article
• ISSN: 0022-3549
• DOI: 10.1002/jps.20787

✦ Synopsis

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-PK 1 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 [ 3 H]daunorubicin, [ 3 H]digoxin, and [mebmt-b-3 H]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 IC 50 value (quinidine IC 50 /verapamil IC 50 ) 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 IC 50 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.