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

Jpn J Cancer Res. 1999 Dec;90(12):1380-6. doi: 10.1111/j.1349-7006.1999.tb00723.x.

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 MDR1 cDNA 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Animals
  • Antineoplastic Agents, Phytogenic / pharmacokinetics*
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Biological Transport, Active / drug effects
  • Cell Line
  • DNA, Complementary / genetics
  • DNA, Complementary / metabolism
  • Docetaxel
  • Drug Resistance, Multiple
  • Humans
  • Intracellular Fluid / drug effects
  • Intracellular Fluid / metabolism
  • Kidney / cytology
  • Paclitaxel / analogs & derivatives*
  • Paclitaxel / pharmacokinetics
  • Paclitaxel / pharmacology
  • Swine
  • Taxoids*
  • Transfection

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antineoplastic Agents, Phytogenic
  • DNA, Complementary
  • Taxoids
  • Docetaxel
  • Paclitaxel