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Intestinal P-glycoprotein inhibitors, benzoxanthone analogues

Title
Intestinal P-glycoprotein inhibitors, benzoxanthone analogues
Authors
Chae, Song WhaLee, JaeokPark, Jung HyunKwon, YoungjooNa, YounghwaLee, Hwa Jeong
Ewha Authors
이화정권영주
SCOPUS Author ID
이화정scopus; 권영주scopus
Issue Date
2018
Journal Title
JOURNAL OF PHARMACY AND PHARMACOLOGY
ISSN
0022-3573JCR Link2042-7158JCR Link
Citation
vol. 70, no. 2, pp. 234 - 241
Keywords
benzoxanthone analogueintestinal P-glycoproteinoral administrationP-glycoprotein inhibitorpharmacokinetics
Publisher
WILEY
Indexed
SCI; SCIE; SCOPUS WOS
Abstract
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.
DOI
10.1111/jphp.12832
Appears in Collections:
약학대학 > 약학과 > Journal papers
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