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

Katsuro Shirakawa, Kohji Takara, Yusuke Tanigawara, Nobuo Aoyama, Masato Kasuga, Fusao Komada, Toshiyuki Sakaeda, Katsuhiko Okumura

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65 Citations (Scopus)

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-GAS-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-GAS-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.

Original languageEnglish
Pages (from-to)1380-1386
Number of pages7
JournalJapanese Journal of Cancer Research
Volume90
Issue number12
DOIs
Publication statusPublished - 1999 Dec

Keywords

  • 'Taxotere'
  • Docetaxel
  • Multidrug resistance
  • P-glycoprotein
  • Transport

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Shirakawa, K., Takara, K., Tanigawara, Y., Aoyama, N., Kasuga, M., Komada, F., Sakaeda, T., & Okumura, K. (1999). Interaction of docetaxel ('Taxotere') with human P-glycoprotein. Japanese Journal of Cancer Research, 90(12), 1380-1386. https://doi.org/10.1111/j.1349-7006.1999.tb00723.x