The inhibitory effects of nicardipine, nifedipine and itraconazole on P- glycoprotein-mediated transport of [3H]digoxin were examined using LLC-PK1 and LLC-GA5-COL150 cells, a porcine kidney epithelial LLC-PK1 cell line transformed with MDR1 cDNA from man which results in overexpression of P- glycoprotein on the apical membrane. Basal-to-apical transport of [3H]digoxin in LLC-GA5-COL150 cells was higher than in LLC-PK1 cells; apical-to-basal transport was markedly lower in LLC-PK1 cells and even lower in LLC-GA5-COL150 cells. This is consistent with the possibility that [3H]digoxin is transported by P-glycoprotein. Co-administration of nicardipine or itraconazole markedly inhibited the basal-to-apical transport of [3H]digoxin in LLC-GA5-COL150 cells, and apical-to-basal transport also increased. The effect of nifedipine was less marked than that of nicardipine or itraconazole. Intracellular accumulation of [3H]digoxin after apical application in LLC-GA5-COL150 cells was 2.3 times less than in LLC-PK1 cells, and was increased by the addition of nicardipine or itraconazole, consistent with their inhibitory effects on transcellular transport. Following basal application of [3H]digoxin, its intracellular accumulation in LLC-GA5-COL150 cells was, unexpectedly, comparable with that in LLC-PK1 cells, and was hardly affected by the addition of nicardipine or itraconazole. In conclusion, it has been shown that nicardipine and itraconazole inhibited transport of digoxin, which is presumably mediated by P-glycoprotein. This explains their effects observed in clinical use.
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