Interaction of docetaxel ("Taxotere") with human P-glycoprotein.

Abstract

The interaction of docetaxel (“Taxotere”) with P‐glycoprotein (P‐gp) was examined using porcine kidney epithelial LLC‐PK1 and LLC‐GA5‐COL150 cells, overexpressing human P‐gp selectively on the apical plasma membrane by transfection of human MDR1cDNA into the LLC‐PK1 cells. The basal‐to‐apical transport of [14C]docetaxel in LLC‐GA5‐COL150 cells significantly exceeded that in LLC‐PK1 cells, but the apical‐to‐basal transport was decreased in LLC‐GA5‐COL150 cells. The intracellular accumulation after its basal or apical application to LLC‐GA5‐COL150 cells was 4‐ to 20‐fold lower than that of LLC‐PK1 cells. Multidrug resistance (MDR) modulators, i.e., cyclosporin A and SDZ PSC 833, inhibited the basal‐to‐apical transport and increased the apical‐to‐basal transport of [14C] docetaxel in LLC‐GA5‐COL150 cells, but verapamil affected only apical‐to‐basal transport. The intracellular accumulation after basal or apical application to LLC‐GA5‐COL150 cells was also increased by these three MDR modulators. These observations demonstrated that docetaxel is a substrate for human P‐gp, suggesting that docetaxel‐drug interactions occur via P‐gp. The inhibition of [14C]docetaxel transport by the MDR modulators, as well as daunorubicin and vinblastine, was also found in LLC‐PK1 cells, which endogenously express P‐gp at lower levels, and concentrations showing similar levels of inhibition were lower than those in the case of LLC‐GA5‐COL150 cells. These observations indicate that it is necessary to consider the Pharmacokinetic and pharmacodynamic interactions of docetaxel via P‐gp.