| Autor: |
Han SY; College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University_Seoul, Goyang-si, Republic of Korea., Kim ES; College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University_Seoul, Goyang-si, Republic of Korea., You BH; College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University_Seoul, Goyang-si, Republic of Korea., Chae HS; College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University_Seoul, Goyang-si, Republic of Korea., Lu Q; College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University_Seoul, Goyang-si, Republic of Korea., Chin YW; College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea., Ahn HC; College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University_Seoul, Goyang-si, Republic of Korea., Chung SJ; College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea., Lee K; College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University_Seoul, Goyang-si, Republic of Korea., Choi YH; College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University_Seoul, Goyang-si, Republic of Korea. |
| Abstrakt: |
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. |
