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

Abstract

1. 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.

2. 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.

3. 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 absorption. LC478 might competitively inhibit P-gp considering its stimulated ATPase activity and its binding site with nucleotide binding domain of P-gp.

4. Therefore, repeated treatment with LC478 can determine its feasibility for P-gp inhibition and changing docetaxel bioavailability.

Keywords:

• LC478
• repeated treatment
• P-glycoprotein
• ATPase activity
• docetaxel
• absorption
• bioavailability

Disclosure statement

The authors report no conflict of interest.

Additional information

Funding

This study was supported National Research Foundation of Korea (NRF) grants funded by the Korea Government (MSIT) [NRF‐2016R1C1B2010849 and NRF 2018R1A5A2023127].