抄録
Itraconazole is known to interact with digoxin, a substrate of P-glycoprotein, in clinical situations. In this study, the interactions of the azole antifungal agents, miconazole, fluconazole, ketoconazole as well as itraconazole, with P-glycoprotein were examined using a transfected kidney epithelial cell line, LLC-GA5-COL150, which expresses human P-glycoprotein on the apical membrane.
Itraconazole decreased the transcellular transport of digoxin from the basolateral to apical side in LLC-GA5-COL150 cell monolayers, that was accompanied by increased cellular accumulation. The basolateralto-apical transcellular transport of digoxin in the host LLC-PK1 cell monolayers was not affected by itraconazole. Ketoconazole and fluconazole also significantly inhibited P-glycoprotein-mediated transport of digoxin, although miconazole was not effective. The inhibitory effects of itraconazole and ketoconazole on digoxin transport in LLC-GA5-COL150 monolayers were as strong as that of cyclosporin A, a typical P-glycoprotein modulator, and neither quinidine nor cimetidine inhibited digoxin transport at the same concentration (10 μM). In addition, the viability of LLC-GA5-COL150 cells against itraconazole was higher than that of LLC-PK1 cells, but viability against the other three azoles was similar to that of LLC-PK1 cells.
In conclusion, ketoconazole and fluconazole as well as itraconazole inhibited the transport of digoxin via human P-glycoprotein, and itraconazole could be a substrate of P-glycoprotein.
