Intestinal P-glycoprotein inhibitors, benzoxanthone analogues

Abstract

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.

Effects of Piperazine Derivative on Paclitaxel Pharmacokinetics

“…Previously, we examined P-gp inhibitory effect of a positive control, VER at two different concentrations (50 and 100 uM) in in vitro studies. Because VER at the concentration of 50 uM did not fully inhibit P-gp function, as compared to 100 uM concentration, based on the results of cytotoxicity and uptake studies [9,27], the cells were treated with 100 uM of the piperazine derivatives and VER to investigate their P-gp inhibitory activity in this study. Among the four piperazine derivatives, the chemical structures of compounds 2–4 were similar (Figure 1).…”

“…The changes in IC 50 values of DNM, P-gp substrate anticancer drug were estimated in the presence of piperazine derivatives at a concentration of 100 μM. The details of the cytotoxicity assay were described in our previous report [9,21]. Verapamil (VER), a representative P-gp substrate and inhibitor, was used as a positive control at a concentration of 100 μM.…”

“…The uptake and efflux values based on the radioactivity estimated by Liquid Scintillation Counting were normalized to those of 1 × 10 6 cells. The detailed procedures have been reported previously [9,21,23]. All the experiments were performed in triplicate and verapamil (VER) was used as a positive control.…”

“…Using human P-gp membrane, the P-gp ATPase activity of pre-selected derivatives, compounds 2 and 4, was estimated at a concentration of 100 μM [9,21,23]. The rate of phosphate release per mg membrane protein represented the ATPase activity by converting to the relative ratio versus control value.…”

“…It has also been reported that approximately 50% of orally administered PTX is excluded from the GI track by P-glycoprotein (P-gp) [3]. There have been many studies on how to improve the bioavailability (BA) of PTX by inhibiting P-gp function and expression over the last two decades [2,4,5,6,7,8,9].…”