Intestinal P-glycoprotein inhibitors, benzoxanthone analogues.
J Pharm Pharmacol
; 70(2): 234-241, 2018 Feb.
Article
em En
| MEDLINE
| ID: mdl-29238994
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 [3 H]-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.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Daunorrubicina
/
Paclitaxel
/
Membro 1 da Subfamília B de Cassetes de Ligação de ATP
/
Xantonas
/
Absorção Intestinal
/
Intestinos
/
Antineoplásicos
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article