Effect of treatment period with LC478, a disubstituted adamantayl derivative, on P-glycoprotein inhibition: its application to increase docetaxel absorption in rats.

Effect of treatment period with LC478, a disubstituted adamantayl derivative, on P-glycoprotein inhibition: its application to increase docetaxel absorption in rats.
Xenobiotica. 2019 Dec 02;:1-43
Authors: Han SY, Kim ES, You BH, Chae HS, Liu Q, Chin YW, Ahn HC, Chung SJ, Lee K, Choi YH
Abstract
Treatment periods of P-glycoprotein (P-gp) inhibitors have revealed different efficacies. We have previously reported dose-dependent inhibition of P-gp in single-treatment with LC478. However, whether repeated treatment with LC478 can inhibit P-gp even at its ineffective single-treatment dose remains unknown. Therefore, the purpose of this study was to assess the effect of repeated treatment (i.e., 7-day treatment) with LC478 on P-gp known to affect docetaxel bioavailability in rats. Effects of LC478 on P-gp mediated efflux and expression in MDCK-MDR1 cells, P-gp ATPase activity, and binding site with P-gp were evaluated.The 7-day treatment with LC478 increased docetaxel absorption via intestinal P-gp inhibition in rats. Intestinal concentrations of LC478 were 8.31-10.3 μM in rats after 7-day treatment of LC478. These concentrations were close to 10 μM that reduced P-gp mediated docetaxel efflux and P-gp expression in MDCK-MDR1 cells. Considering that intestinal LC478 concentrations after 1-day treatment were 2.68-4.19 μM, higher LC478 concentrations after 7-day treatment might have driven P-gp inhibition and increased docetaxel abso...

Source: Xenobiotica - December 1, 2019 Category: Research Authors: Han SY, Kim ES, You BH, Chae HS, Liu Q, Chin YW, Ahn HC, Chung SJ, Lee K, Choi YH Tags: Xenobiotica Source Type: research