Time-dependent changes in the activation of RhoA/ROCK and ERM/p-ERM in the increased expression of intestinal P-glycoprotein by repeated oral treatment with etoposide

Authors

  • Takuro Kobori,

    1. Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kobe Gakuin University, Chuo-ku, Kobe 650-8586, Japan
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  • Shinichi Harada,

    1. Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kobe Gakuin University, Chuo-ku, Kobe 650-8586, Japan
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  • Kazuo Nakamoto,

    1. Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kobe Gakuin University, Chuo-ku, Kobe 650-8586, Japan
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  • Shogo Tokuyama

    Corresponding author
    1. Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kobe Gakuin University, Chuo-ku, Kobe 650-8586, Japan
    • Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kobe Gakuin University, Chuo-ku, Kobe 650-8586, Japan. Telephone: +81-78-974-4780; Fax: +81-78-974-4780
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Abstract

Previously, we reported that repeated oral treatment with etoposide (ETP) increased ileal membrane localization of P-glycoprotein (P-gp) and that this was possibly mediated by increased expression of the ezrin/radixin/moesin (ERM)/phosphorylated ERM (p-ERM) via activation of RhoA/ROCK. These changes caused decreases in the analgesia of oral morphine (substrate drug for P-gp). However, there are no reports indicating the temporal changes in the above-mentioned factors after initiation and cessation of repeated treatment with the substrate drugs for P-gp including ETP. We examined the relationships between time-dependent changes in protein expressions of ileal P-gp and those of RhoA, ROCK, ERM, and p-ERM, and in oral morphine analgesia after initiation or cessation of repeated oral treatment with ETP. Ileal membrane localization of RhoA was increased 3 days after initiating ETP treatment; on 5 or 7 days, that of ROCK, ERM, and p-ERM was increased along with increments in P-gp expression, leading to decreases in oral morphine analgesia. All these changes returned toward normal levels 3 days after cessation. These data suggest that regulating the active state of the above-mentioned proteins during cancer chemotherapy or creating a timeframe of discontinuation a few days after cessation may enable effective palliative care using oral opioids. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:1670–1682, 2013

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