title: Pharmacokinetic compatibility of ginsenosides and Schisandra Lignans in Shengmai-san: from the perspective of p-glycoprotein.
abstract: BACKGROUND
  Phytochemical-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.
  
  
  METHODS
  Pharmacokinetic 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.
  
  
  CONCLUSIONS
  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, 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.
authors.affiliation: Key Lab of Drug Metabolism & Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu Province, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Key Lab of Drug Metabolism & Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu Province, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Key Lab of Drug Metabolism & Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu Province, China.
authors.forename: Jingwei
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Key Lab of Drug Metabolism & Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu Province, China.
authors.forename: Tai
authors.initials: T
authors.lastname: Rao
authors.affiliation: Key Lab of Drug Metabolism & Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu Province, China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Key Lab of Drug Metabolism & Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu Province, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Xing
authors.affiliation: Key Lab of Drug Metabolism & Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu Province, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Key Lab of Drug Metabolism & Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu Province, China.
authors.forename: Hanxu
authors.initials: H
authors.lastname: Fu
authors.affiliation: Key Lab of Drug Metabolism & Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu Province, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Hao
authors.affiliation: Key Lab of Drug Metabolism & Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu Province, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Xie
authors.affiliation: Key Lab of Drug Metabolism & Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu Province, China.
authors.forename: Guangji
authors.initials: G
authors.lastname: Wang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D018938:Caco-2 Cells; D002316:Cardiotonic Agents / Q000097:blood*; D004077:Digoxin / Q000097:blood; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D036145:Ginsenosides / Q000097:blood*; D041743:Herb-Drug Interactions; D006801:Humans; D051381:Rats
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002316:Cardiotonic Agents; D004365:Drugs, Chinese Herbal; D036145:Ginsenosides; D004077:Digoxin