Effect of coumarin derivative-mediated inhibition of P-glycoprotein on oral bioavailability and therapeutic efficacy of paclitaxel

Kyeong Lee, Song Wha Chae, Yan Xia, Na Hyung Kim, Hyun Ju Kim, Sandy Rhie, Hwa Jeong Lee

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Since P-glycoprotein (P-gp) acts as a barrier to intestinal absorption of various drugs, P-gp inhibitors have been studied as oral absorption enhancers of P-gp substrate drugs. Here, we investigated the in vitro and in vivo effects of a novel coumarin derivative (LL-348) for its P-gp inhibitory activity. With LL-348, accumulation of daunomycin (DNM) increased 270% and efflux of DNM decreased 63% compared to that of DNM alone. Paclitaxel (PTX, 25 mg/kg) after oral administration with LL-348 (5 mg/kg), the optimal dose of LL-348 as an oral absorption enhancer of PTX, improved the relative bioavailability (RB) of PTX to 961%. In a xenograft animal model, PTX (40 mg/kg) treated with LL-348 (10 mg/kg) significantly increased the efficacy of PTX. The results collectively demonstrate that LL-348 can provide a therapeutic benefit in the oral absorption of P-gp substrate anticancer drugs

Original languageEnglish
Pages (from-to)381-388
Number of pages8
JournalEuropean Journal of Pharmacology
Volume723
Issue number1
DOIs
StatePublished - 15 Jan 2014

Bibliographical note

Funding Information:
This work was supported by the National Research Foundation of Korea (NRF) Grant funded by the Korean Government (MEST) (Basic Science Research Program: 2012-0004439 , Bio & Medical Technology Development Program: no. 2012M3A9C1053532 ).

Keywords

  • Bioavailability
  • Coumarin derivative
  • Daunomycin
  • P-glycoprotein
  • Paclitaxel
  • Xenograft

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