Intestinal P-glycoprotein inhibitors, benzoxanthone analogues
- 주제(키워드) benzoxanthone analogue , intestinal P-glycoprotein , oral administration , P-glycoprotein inhibitor , pharmacokinetics
- 주제(기타) Pharmacology & Pharmacy
- 설명문(일반) [Chae, Song Wha; Lee, Jaeok; Park, Jung Hyun; Kwon, Youngjoo; Lee, Hwa Jeong] Ewha Womans Univ, Grad Sch Pharmaceut Sci, Seoul 03760, South Korea; [Na, Younghwa] CHA Univ, Coll Pharm, Pochon 487010, South Korea
- 등재 SCIE, SCOPUS
- 발행기관 WILEY
- 발행년도 2018
- URI http://www.dcollection.net/handler/ewha/000000150097
- 본문언어 영어
- Published As http://dx.doi.org/10.1111/jphp.12832
초록/요약
Objectives: The inhibitors of P-glycoprotein (P-gp) which limits an access of exogenous compounds in the luminal membrane of the intestine have been studied to enhance the intestinal P-gp-mediated absorption of anticancer drugs. Methods: Inhibition of the efflux pump by synthesized benzoxanthone derivatives was investigated in vitro and in vivo. MCF-7/ADR cell line was used for cytotoxicity assay and [H-3]-daunomycin (DNM) accumulation/efflux study. Eight benzoxanthone analogues were tested for their effects on DNM cytotoxicity. Among them, three analogues were selected for the accumulation/efflux and P-gp ATPase studies. Paclitaxel (PTX), a P-gp substrate anticancer drug, was orally administered to rats with/without compound 1 (8,10-bis(thiiran-2-ylmethoxy)-7H-benzo[c]xanthen-7-one). The pharmacokinetic parameters of PTX in the presence/absence of compound 1 were evaluated from the plasma concentration-time profiles. Key-findings: Compound 1 increased the DNA accumulation to 6.5-fold and decreased the DNM efflux to approximately 1/2 in the overexpressing P-gp cell line. Relative bioavailability (RB) of PTX in rats was significantly increased up to 3.2-fold by compound 1 (0.5 or 2 mg/kg). Conclusions: Benzoxanthone analogue, compound 1 is strongly suggested to be a promising inhibitor of P-gp to improve an oral absorption of compounds for cancer therapy.
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