Cellular pharmacokinetic aspects of reversal effect of itraconazole on P-glycoprotein-mediated resistance of anticancer drugs

Kohji Takara, Yusuke Tanigawara, Fusao Komada, Kohshi Nishiguchi, Toshiyuki Sakaeda, Katsuhiko Okumura

研究成果: Article査読

56 被引用数 (Scopus)

抄録

The reversal effect of itraconazole on P-glycoprotein (P-gp)-mediated resistance of vinblastine, daunorubicin and doxorubicin was analyzed from a cellular pharmacokinetic point of view, namely by [3H]azidopine photoaffinity labeling, intracellular accumulation and transcellular transport experiments. The LLC-GA5COL150 cells, which expressed human P-gp selectively on the apical membrane due to transfection of MDR1 cDNA into the porcine kidney epithelial cells (LLC-PK1 cells), was used here, since this cell line constructs the monolayer with tight junction, being able to characterize the cellular pharmacokinetics. In LLC-GA5-COL150 cells, itraconazole caused a reversal from resistance as shown by a growth inhibition assay. [3H]Azidopine photoaffinity labeling demonstrated that itraconazole, vinblastine, daunorubicin and doxorubicin showed higher binding ability for P-gp compared with digoxin, suggesting the following results were via P-gp. The intracellular accumulation of [3H]vinblastine, [3H]daunorubicin and [14C]doxorubicin after their application on the basal and apical sides was increased by itraconazole. These changes were similar to the dose modifying factors determined by the growth inhibition assay. However, their basal-to-apical transport was hardly affected by itraconazole, and this was explained by the fact that itraconazole inhibited P-gp, and subsequently increased their intracellular concentration and then the non-P- gp mediated transport from the intracellular space to apical side. The apicalto-basal transport of [3H]vinblastine, [3H]daunorubicin and [14C]doxorubicin was increased by itraconazole, and this was reasonably explained by the inhibition of P-gp, and partly also by the increase of their intracellular concentration via the inhibition of P-gp.

本文言語English
ページ(範囲)1355-1359
ページ数5
ジャーナルBiological and Pharmaceutical Bulletin
22
12
DOI
出版ステータスPublished - 1999 12

ASJC Scopus subject areas

  • 薬理学
  • 薬科学

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