Abstract
P-glycoprotein (P-gp)-mediated efflux of docetaxel in the gastrointestinal tract mainly impedes its oral chemotherapy. Recently, LC478, a novel di-substituted adamantyl derivative, was identified as a non-cytotoxic P-gp inhibitor in vitro. Here, we assessed whether LC478 enhances the oral bioavailability of docetaxel in vitro and in vivo. LC478 inhibited P-gp mediated efflux of docetaxel in Caco-2 cells. In addition, 100 mg/kg of LC478 increased intestinal absorption of docetaxel, which led to an increase in area under plasma concentration-time curve (AUC) and absolute bioavailability of docetaxel in rats. According to U.S. FDA criteria (I, an inhibitor concentration in vivo tissue)/(IC50, inhibitory constant in vitro) >10 determines P-gp inhibition between in vitro and in vivo. The values 15.6–20.5, from (LC478 concentration in intestine, 9.37–12.3 μM)/(IC50 of LC478 on P-gp inhibition in Caco-2 cell, 0.601 μM) suggested that 100 mg/kg of LC478 sufficiently inhibited P-gp to enhance oral absorption of docetaxel. Moreover, LC478 inhibited P-gp mediated efflux of docetaxel in the ussing chamber studies using rat small intestines. Our study demonstrated that the feasibility of LC478 as an ideal enhancer of docetaxel bioavailability by P-gp inhibition in dose (concentration)-dependent manners.
Highlights
Docetaxel, a second-generation taxane, has significant and broad anti-tumor activities against breast, ovary, prostate, non-small cell lung, and gastric cancers [1,2]
The low oral bioavailability of docetaxel impedes its clinical application of oral chemotherapy owing to its physiochemical properties and its physiological barriers (e.g., pre-systemic metabolism via cytochrome P450 (CYP)3A and transmembrane efflux via P-glycoprotein (P-gp)) [2,5,10,11,12,13,14,15]
To examine the effect of LC478 on P-gp activity, rhodamine-123 transmembrane efflux was efflux of rhodamine-123 represented by secretory Papp values, and its activity was decreased to 136%
Summary
A second-generation taxane, has significant and broad anti-tumor activities against breast, ovary, prostate, non-small cell lung, and gastric cancers [1,2]. Oral docetaxel chemotherapy is a desired alternative regimen [5,6] in terms of administration convenience, better patient compliance, and prolonged systemic exposure profile with less fluctuation [7,8,9]. The low oral bioavailability of docetaxel (less than 5% of the oral dose) impedes its clinical application of oral chemotherapy owing to its physiochemical properties (e.g., low water solubility and membrane permeability) and its physiological barriers ATP-binding cassette (ABC) transporters (e.g., P-gp, multidrug resistance-associated protein 1 (MRP1), MRP2 and breast cancer resistance protein (BCRP) transporters) in enterocytes or hepatocytes and human solute carrier (SLC) transporters
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