A pharmacokinetic and pharmacodynamic study of drug-drug interaction between ginsenoside Rg1, ginsenoside Rb1 and schizandrin after intravenous administration to rats.
BACKGROUND
Ginsenoside Rg1, ginsenoside Rb1 and schizandrin are main bioactive components from Panax ginseng and Schisandra chinensis. They have been found in many prescriptions of Traditional Chinese Medicines (TCM) and proven to be effective for prevention and treatment of cardiovascular disease. It is valuable to investigate their pharmacokinetic and pharmacodynamic behavior and potential synergistic effect for better drug development and clinical application.


METHODS
Pharmacokinetic and nitric oxide (NO) release pharmacodynamic drug-drug interactions of ginsenoside Rg1, ginsenoside Rb1 and schisandrin were studied after intravenous administration of each compound with the dose of 10 mg/kg and their mixture with the total dose of 10 mg/kg to isoproterenol (ISO)-induced myocardial ischemia rats. Drug concentrations in serum were determined using LC-MS method. Nitrite and nitrate (NOx(-)), the predominant oxidation product of NO in serum was used as an effective marker and quantitated by the method of high-performance liquid chromatography coupled with fluorescence detection (HPLC-FL). The main pharmacokinetic parameters of T(1/2β), MRT(0-∞), Vd, Cl, and AUC, and the main pharmacodynamic parameters of Cmax, Tmax and AUEC were calculated by non-compartment model.


RESULTS
The results indicated ginsenoside Rb1 and (or) schisandrin in mixture could significantly postpone the elimination of ginsenoside Rg1 in rat serum. Co-administration of three compounds markedly increased the systemic exposure level of each compound in vivo. Ginsenoside Rg1 and ginsenoside Rb1 had the effect of inducing real-time NO release in rats concentration dependently. Schisandrin had no effect of inducing real-time NO release in this study. The mixture of ginsenoside Rg1, Rb1 and schisandrin administration exhibited synergistic effect of inducing NO release in ISO treated rats.


CONCLUSIONS
The result obtained from this study suggested pharmacokinetic and pharmacodynamic drug-drug interactions between ginsenoside Rg1, Rb1 and schisandrin. The study provided valuable information for drug development and clinical application of TCM.
Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Shuyu
S
Zhan
Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Wenjing
W
Guo
Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Qing
Q
Shao
Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address: fanxh@zju.edu.cn.
Xiaohui
X
Fan
State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China. Electronic address: lizheng1@gmail.com.
Zheng
Z
Li
Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Yiyu
Y
Cheng
D061605:Administration, Intravenous; D000818:Animals; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D034242:Cyclooctanes / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D004347:Drug Interactions; D004357:Drug Synergism; D036145:Ginsenosides / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D006207:Half-Life; D017705:Lignans / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D008516:Medicine, Chinese Traditional; D008954:Models, Biological; D009569:Nitric Oxide / Q000378:metabolism; D005894:Panax / Q000737:chemistry; D011083:Polycyclic Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D032141:Schisandra / Q000737:chemistry
D034242:Cyclooctanes; D036145:Ginsenosides; D017705:Lignans; D011083:Polycyclic Compounds; D009569:Nitric Oxide; C442759:ginsenoside Rb1; C011105:schizandrin; C035054:ginsenoside Rg1
Ginsenoside Rb1; Ginsenoside Rg1; Nitric oxide; Pharmacodynamics; Pharmacokinetic interaction; Schisandrin