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Intestinal P-glycoprotein inhibitors, benzoxanthone analogues
- Intestinal P-glycoprotein inhibitors, benzoxanthone analogues
- Chae, Song Wha; Lee, Jaeok; Park, Jung Hyun; Kwon, Youngjoo; Na, Younghwa; Lee, Hwa Jeong
- Ewha Authors
- 이화정; 권영주; 이재옥
- SCOPUS Author ID
- 이화정; 권영주; 이재옥
- Issue Date
- Journal Title
- JOURNAL OF PHARMACY AND PHARMACOLOGY
- JOURNAL OF PHARMACY AND PHARMACOLOGY vol. 70, no. 2, pp. 234 - 241
- benzoxanthone analogue; intestinal P-glycoprotein; oral administration; P-glycoprotein inhibitor; pharmacokinetics
- SCIE; SCOPUS
- Document Type
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- 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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