Pharmacokinetic Compatibility of Ginsenosides and <i>Schisandra</i> Lignans in <i>Shengmai-san</i>: From the Perspective of P-Glycoprotein

<div><p>Background</p><p>Phytochemical-mediated alterations in P-glycoprotein (P-gp) activity may result in herb-drug interactions by altering drug pharmacokinetics. <i>Shengmai-san</i>, a traditional Chinese herbal medicine composed by <i>Panax Ginseng, Ophiopogon Japonicus, and Schisandra Chinensis</i>, is routinely being used for treating various coronary heart diseases. In our previous studies, S<i>chisandra Lignans Extract</i> (SLE) was proved as a strong P-gp inhibitor, and herein, the compatibility of <i>Shengmai-san</i> was studied by investigating the influence of SLE on the pharmacokinetics of the ginsenosides from the perspective of P-gp.</p><p>Methodology</p><p>Pharmacokinetic experiments were firstly performed based on <i>in vitro</i> uptake, efflux and transport experiments in Caco-2, LLC-PK1 wild-type and MDR1-overexpressing L-MDR1 cells. During the whole experiment, digoxin, a classical P-gp substrate, was used as a positive control drug to verify the cells used are the valid models. Meanwhile, the effects of SLE on the pharmacokinetics of ginsenosides were further investigated in rats after single-dose and multi-dose of SLE.</p><p>Results and Conclusions</p><p>The efflux ratios of ginsenoside Rb2, Rc, Rg2, Rg3, Rd and Rb1 were found more than 3.5 in L-MDR1 cells and can be decreased significantly by verapamil (a classical P-gp inhibitor). Contrarily, the efflux ratios of other ginsenosides (Rh1, F1, Re, and Rg1) were lower than 2.0 and not affected by verapamil. Then, the effects of SLE on the uptake and transport of ginsenosides were investigated, and SLE was found can significantly enhance the uptake and inhibit the efflux ratio of ginsenoside Rb2, Rc, Rg2, Rg3, Rd and Rb1 in Caco-2 and L-MDR1 cells. Besides, <i>In vivo</i> experiments showed that single-dose and multi-dose of SLE at 500 mg/kg could increase the area under the plasma concentration time curve of Rb2, Rc and Rd significantly without affecting terminal elimination half-time. In conclusion, SLE could enhance the exposure of ginsenosides Rb2, Rc, Rg2, Rg3, Rd and Rb1 significantly.</p></div

The pharmacokinetic parameters of digoxin and ginsenoside Rb1, Rb2, Rc and Rd after multiple ig SLE and 150/kg GE in rats (n = 5).

<p>The pharmacokinetic parameters of digoxin and ginsenoside Rb1, Rb2, Rc and Rd after multiple ig SLE and 150/kg GE in rats (n = 5).</p

The effect of verapamil on the uptake of ginsenosides in LLC-PK1 and L-MDR1 cell and the effect of verapamil on the uptake and transport of digoxin and ginsenosides in Caco-2 cell.

<p>(A) The concentration of digoxin and ginsenosides in LLC-PK1 cell in the absence and presence of verapamil. (B) The concentration of digoxin and ginsenosides in L-MDR1 cell in the absence and presence of verapamil. (C) The concentration of digoxin and ginsenosides in Caco-2 cell in the absence and presence of verapamil. (D) The efflux ratio of digoxin and ginsenosides on Caco-2 cells in the absence and presence of verapamil.</p

The effect of verapamil on the efflux ratio of digoxin, ginsenoside Rh1, F1, Rb2, Rc, Rg2, Rg3, Re, Rd, Rb1 and Rg1 on LLC-PK1 and L-MDR1 cell.

<p>(A) The efflux ratio of digoxin and ginsenosides on LLC-PK1 cells in the absence and presence of verapamil. (B) The efflux ratio of digoxin and ginsenosides on L-MDR1cells in the absence and presence of verapamil.</p

The systematic workflow of this study.

<p>The systematic workflow of this study.</p

The effect of SLE on the uptake and transport of digoxin and ginsenosides in LLC-PK1 and L-MDR1 cell.

<p>(A) The transport of digoxin and ginsenosides on LLC-PK1 cell in the absence and presence of SLE at 2.0 µg/mL (L) and 10.0 µg/mL (H). (B) The transport of digoxin and ginsenosides on L-MDR1 cell in the absence and presence of SLE at 2.0 µg/mL (L) and 10.0 µg/mL (H). (C) The concentration of digoxin and ginsenosides in LLC-PK1 cell in the absence and presence of SLE at 2.0 µg/mL (L) and 10.0 µg/mL (H). (D) The concentration of digoxin and ginsenosides in L-MDR1 cell in the absence and presence of SLE at 2.0 µg/mL (L) and 10.0 µg/mL (H).</p

The plasma concentration-time profiles of digoxin and ginsenoside Rb1, Rb2, Rc and Rd after multi-dose of vehicle / SLE and GE.

<p>The plasma concentration-time profiles of digoxin and ginsenoside Rb1, Rb2, Rc and Rd after multi-dose of vehicle / SLE and GE.</p

The plasma concentration-time profiles of digoxin and ginsenoside Rb1, Rb2, Rc and Rd after single-dose of vehicle / SLE and GE.

<p>The plasma concentration-time profiles of digoxin and ginsenoside Rb1, Rb2, Rc and Rd after single-dose of vehicle / SLE and GE.</p

The effect of SLE on the transport and uptake of digoxin and ginsenosides in Caco-2 cell.

<p>(A) The transport of digoxin and ginsenosides on Caco-2 cell in the absence and presence of SLE at 2.0 µg/mL (L) and 10.0 µg/mL (H). (B) The uptake of digoxin and ginsenosides in Caco-2 cell in the absence and presence of SLE at 2.0 µg/mL (L) and 10.0 µg/mL (H).</p