Abstract
BackgroundPhytochemical-mediated alterations in P-glycoprotein (P-gp) activity may result in herb-drug interactions by altering drug pharmacokinetics. Shengmai-san, a traditional Chinese herbal medicine composed by Panax Ginseng, Ophiopogon Japonicus, and Schisandra Chinensis, is routinely being used for treating various coronary heart diseases. In our previous studies, Schisandra Lignans Extract (SLE) was proved as a strong P-gp inhibitor, and herein, the compatibility of Shengmai-san was studied by investigating the influence of SLE on the pharmacokinetics of the ginsenosides from the perspective of P-gp.MethodologyPharmacokinetic experiments were firstly performed based on in vitro 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.Results and ConclusionsThe 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, In vivo 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.
Highlights
Traditional Chinese medicine (TCM) has been utilized in the Chinese culture to treat the complex of symptoms for thousands of years [1,2]
In order to identify whether ginsenosides are P-gp substrates or not, we compared the effect of a classical P-gp inhibitor on the transport / uptake abilities of ginsenosides in LLC-PK1 cells and the derived cell line L-MDR1
In the tide of the modernization of Chinese medicine, combined application of TCM can achieve a synergistic interaction capable of yielding more distinct effect at lower doses than that produced by single Chinese herbal medicine [33]
Summary
Traditional Chinese medicine (TCM) has been utilized in the Chinese culture to treat the complex of symptoms for thousands of years [1,2]. ‘‘assistant’’ drug is used to promote ‘‘minister’’ drug treat the chief syndromes / disease, or to aim at minor symptoms, and the ‘‘messenger’’ drug mainly used to modulate the interactions among the herbs [7,8]. There was an increasing focus on the compatibility study for TCM based on pharmacokinetic interaction among herbs [11,12,13]. Shengmai-san, a traditional Chinese herbal medicine composed by Panax Ginseng, Ophiopogon Japonicus, and Schisandra Chinensis, is routinely being used for treating various coronary heart diseases. Schisandra Lignans Extract (SLE) was proved as a strong P-gp inhibitor, and the compatibility of Shengmai-san was studied by investigating the influence of SLE on the pharmacokinetics of the ginsenosides from the perspective of P-gp
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