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.

中文翻译：

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LC478（一种双取代的金刚烷基衍生物）治疗期对P-糖蛋白抑制的影响：其在大鼠中增加多西他赛吸收的应用。

1. P-糖蛋白（P-gp）抑制剂的治疗期显示出不同的疗效。我们以前曾报道过LC478单次治疗对P-gp的剂量依赖性抑制作用。然而，用LC478重复治疗是否即使在无效的单次治疗剂量下也能抑制P-gp仍然未知。2.因此，本研究的目的是评估用LC478重复治疗（即7天治疗）对P-gp的影响，已知该P-gp影响大鼠多西他赛的生物利用度。评估了LC478对P-gp介导的外排和在MDCK-MDR1细胞中表达，P-gp ATP酶活性以及与P-gp结合位点的影响。3。用LC478进行的7天治疗可通过大鼠肠道P-gp抑制作用提高多西他赛的吸收。治疗7天后，大鼠的小肠LC478浓度为8.31-10.3μM。这些浓度接近10μM，可降低MDCK-MDR1细胞中P-gp介导的多西他赛外排和P-gp表达。考虑到1天治疗后肠道LC478的浓度为2.68-4.19μM，因此7天治疗后较高的LC478浓度可能会导致P-gp抑制和多西他赛吸收增加。考虑到其刺激的ATPase活性和与P-gp核苷酸结合域的结合位点，LC478可能竞争性地抑制P-gp。4.因此，用LC478重复治疗可以确定其抑制P-gp和改变多西他赛生物利用度的可行性。治疗7天后更高的LC478浓度可能会导致P-gp抑制和多西他赛吸收增加。考虑到其刺激的ATPase活性和与P-gp核苷酸结合域的结合位点，LC478可能竞争性地抑制P-gp。4.因此，用LC478重复治疗可以确定其抑制P-gp和改变多西他赛生物利用度的可行性。治疗7天后更高的LC478浓度可能会导致P-gp抑制和多西他赛吸收增加。考虑到其刺激的ATPase活性和与P-gp核苷酸结合域的结合位点，LC478可能竞争性地抑制P-gp。4.因此，用LC478重复治疗可以确定其抑制P-gp和改变多西他赛生物利用度的可行性。