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. 2019 Mar 20;11(3):135.
doi: 10.3390/pharmaceutics11030135.

LC478, a Novel Di-Substituted Adamantyl Derivative, Enhances the Oral Bioavailability of Docetaxel in Rats

Seung Yon Han  1 , Qili Lu  2 , Kyeong Lee  3 , Young Hee Choi  4
Affiliations

LC478, a Novel Di-Substituted Adamantyl Derivative, Enhances the Oral Bioavailability of Docetaxel in Rats

Seung Yon Han et al. Pharmaceutics. .

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.

Keywords: LC478; P-glycoprotein; absorption; bioavailability; docetaxel; inhibition.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structure of LC478.
Figure 2
Figure 2
Effect of LC478 on P-gp mediated efflux of rhodamine-123. (A) Absorptive Papp (■) and secretory Papp (■) of rhodamine-123 with LC478 (1 and 10 µM) or verapamil (10 µM) across Caco-2 cells. Vertical bars represent standard deviation (SD) and the number of each group is three. * Significantly different (p < 0.05) from absorptive (M to S) group. # Significantly different (p < 0.05) from the control group. (B) The EC50 curves of verapamil (left) and LC478 (right) on rhodamine-123 accumulation in Caco-2 cells. Vertical bar represents standard error of the mean (SEM) and number of each group is three.
Figure 3
Figure 3
Effect of LC478 on P-gp activity. The EC50 curves of LC478 on docetaxel accumulation in Caco-2 cells. The vertical bar represents SEM and the number of each group is three.
Figure 4
Figure 4
(A) Mean arterial plasma concentration–time profiles of docetaxel after its intravenous administration with 0 (○; n = 6), 30 (●; n = 6) or 100 (▲; n = 6) mg/kg LC478 in rats. (B) Mean arterial plasma concentration–time profiles of docetaxel after its oral administration with 0 (○; n = 5), 30 (●; n = 6), and 100 (▲; n = 6) mg/kg LC478 in rats. Vertical bar represents SD.
Figure 5
Figure 5
Absorptive Papp (■) and secretory Papp (■) of Rhodamine-123 (A) or docetaxel (B) across the rat small intestine with various concentrations of verapamil or LC478. Vertical bar represents SD. * Significantly different (p < 0.05) from absorptive (M to S) group. # Significantly different (p < 0.05) from control group.
Figure 6
Figure 6
The graph for velocity versus docetaxel concentrations in hepatic (A) and intestinal (B) microsomes. Symbols represent LC478 concentrations: 0 (●; n = 3), 1 (○; n = 3), 10 (▼; n = 3) and 50 (∆; n = 3) μM LC478. Vertical bar represents SD.
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