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

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 acti...

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Bibliographic Details
Published in:European journal of pharmacology 2014-01, Vol.723, p.381-388
Main Authors: Lee, Kyeong, Chae, Song Wha, Xia, Yan, Kim, Na Hyung, Kim, Hyun Ju, Rhie, Sandy, Lee, Hwa Jeong
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Antibiotics, Antineoplastic - pharmacology
Antineoplastic Agents, Phytogenic - blood
Antineoplastic Agents, Phytogenic - pharmacokinetics
Antineoplastic Agents, Phytogenic - therapeutic use
ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors
Bioavailability
Biological Availability
Cell Line, Tumor
Cell Survival - drug effects
Coumarin derivative
Coumarins - pharmacology
Daunomycin
Daunorubicin - pharmacology
Humans
Male
Mice
Mice, Nude
Neoplasms - drug therapy
Neoplasms - pathology
P-glycoprotein
Paclitaxel
Paclitaxel - blood
Paclitaxel - pharmacokinetics
Paclitaxel - therapeutic use
Rats
Rats, Sprague-Dawley
Treatment Outcome
Tumor Burden - drug effects
Xenograft
Xenograft Model Antitumor Assays
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Summary: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, 25mg/kg) after oral administration with LL-348 (5mg/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 (40mg/kg) treated with LL-348 (10mg/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
ISSN:0014-2999
1879-0712
DOI:10.1016/j.ejphar.2013.11.002