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

• 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
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2013.11.002

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