Effects of 12 Ca2+ antagonists on multidrug resistance, MDR1-mediated transport and MDR1 mRNA expression

Kohji Takara, Toshiyuki Sakaeda, Yusuke Tanigawara, Kohshi Nishiguchi, Nobuko Ohmoto, Masanori Horinouchi, Fusao Komada, Noriaki Ohnishi, Teruyoshi Yokoyama, Katsuhiko Okumura

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

The effects of 12 Ca2+ antagonists on MDR1 were examined by two independent models: the inhibitory effect on MDR1-mediated transport of [3H]digoxin using MDR1-overexpressing LLC-GA5-COL150 cell monolayers and the reversal effect on cytotoxicity of vinblastine or paclitaxel using MDR1-overexpressing Hvr100-6 cells. The inhibitory effects on [3H]digoxin transport were assessed as the 50% inhibitory concentration during 4 h exposure, and the values were the lowest for nicardipine (4.54 μM), manidipine (4.65 μM) and benidipine (4.96 μM), followed by bepridil (10.6 μM), barnidipine (12.6 μM), efonidipine (13.0 μM), verapamil (13.2 μM) and nilvadipine (18.0 μM). The reversal effect on cytotoxicity was assessed by the 50% growth inhibitory concentration after 3 days exposure, and the resistance to vinblastine or paclitaxel in Hvr100-6 cells was reversed by manidipine, verapamil, benidipine, barnidipine, and nicardipine, in that order. Bepridil, barnidipine, efonidipine, verapamil and nilvadipine showed similar inhibitory effects on [3H]digoxin transport, but barnidipine and verapamil showed a stronger effect in reversal of cytotoxicity. Real-time quantitative RT-PCR assay indicated a decrease in MDR1 mRNA expression by barnidipine and verapamil. It is concluded that Ca2+ antagonists cannot only be direct inhibitors of MDR1 but that some may at the same time act as inhibitors of expression of MDR1 via down-regulation of MDR1 mRNA.

Original languageEnglish
Pages (from-to)159-165
Number of pages7
JournalEuropean Journal of Pharmaceutical Sciences
Volume16
Issue number3
DOIs
Publication statusPublished - 2002

Fingerprint

Multiple Drug Resistance
Verapamil
manidipine
nilvadipine
Digoxin
Messenger RNA
Bepridil
Nicardipine
Vinblastine
Paclitaxel
Inhibitory Concentration 50
Real-Time Polymerase Chain Reaction
Down-Regulation
mepirodipine
Growth
benidipine
efonidipine

Keywords

  • Ca antagonists
  • Down-regulation
  • MDR1
  • Reversal of MDR
  • Transcellular transport

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Effects of 12 Ca2+ antagonists on multidrug resistance, MDR1-mediated transport and MDR1 mRNA expression. / Takara, Kohji; Sakaeda, Toshiyuki; Tanigawara, Yusuke; Nishiguchi, Kohshi; Ohmoto, Nobuko; Horinouchi, Masanori; Komada, Fusao; Ohnishi, Noriaki; Yokoyama, Teruyoshi; Okumura, Katsuhiko.

In: European Journal of Pharmaceutical Sciences, Vol. 16, No. 3, 2002, p. 159-165.

Research output: Contribution to journalArticle

Takara, K, Sakaeda, T, Tanigawara, Y, Nishiguchi, K, Ohmoto, N, Horinouchi, M, Komada, F, Ohnishi, N, Yokoyama, T & Okumura, K 2002, 'Effects of 12 Ca2+ antagonists on multidrug resistance, MDR1-mediated transport and MDR1 mRNA expression', European Journal of Pharmaceutical Sciences, vol. 16, no. 3, pp. 159-165. https://doi.org/10.1016/S0928-0987(02)00082-9
Takara, Kohji ; Sakaeda, Toshiyuki ; Tanigawara, Yusuke ; Nishiguchi, Kohshi ; Ohmoto, Nobuko ; Horinouchi, Masanori ; Komada, Fusao ; Ohnishi, Noriaki ; Yokoyama, Teruyoshi ; Okumura, Katsuhiko. / Effects of 12 Ca2+ antagonists on multidrug resistance, MDR1-mediated transport and MDR1 mRNA expression. In: European Journal of Pharmaceutical Sciences. 2002 ; Vol. 16, No. 3. pp. 159-165.
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