title: Effect of coumarin derivative-mediated inhibition of P-glycoprotein on oral bioavailability and therapeutic efficacy of paclitaxel.
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, 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.
authors.affiliation: College of Pharmacy, Dongguk University-Seoul, Seoul 100-715, Republic of Korea.
authors.forename: Kyeong
authors.initials: K
authors.lastname: Lee
authors.affiliation: College of Pharmacy (Global Top5 Research Program), Ewha Womans University, Seoul 120-750, Republic of Korea.
authors.forename: Song Wha
authors.initials: SW
authors.lastname: Chae
authors.affiliation: College of Pharmacy, Dongguk University-Seoul, Seoul 100-715, Republic of Korea.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48102, USA.
authors.forename: Na Hyung
authors.initials: NH
authors.lastname: Kim
authors.affiliation: College of Pharmacy (Global Top5 Research Program), Ewha Womans University, Seoul 120-750, Republic of Korea.
authors.forename: Hyun Ju
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: College of Pharmacy (Global Top5 Research Program), Ewha Womans University, Seoul 120-750, Republic of Korea.
authors.forename: Sandy
authors.initials: S
authors.lastname: Rhie
authors.affiliation: College of Pharmacy (Global Top5 Research Program), Ewha Womans University, Seoul 120-750, Republic of Korea. Electronic address: hwalee@ewha.ac.kr.
authors.forename: Hwa Jeong
authors.initials: HJ
authors.lastname: Lee
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000284:Administration, Oral; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001682:Biological Availability; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003374:Coumarins / Q000494:pharmacology*; D003630:Daunorubicin / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D017239:Paclitaxel / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D003374:Coumarins; D017239:Paclitaxel; D003630:Daunorubicin
keywords: Bioavailability; Coumarin derivative; Daunomycin; P-glycoprotein; Paclitaxel; Xenograft