| Qing Re Yang Xin granule is the preparation of Jiangsu Province Hospital of TCM, in which the main constituents were honeysuckle, coptis chinensis, glycyrrhiza and lily. Traditionally, the preparation, which was for heat-clearing and detoxifying and hyperactivity nourishing heart to calm mind. Clinically, it has been primarily used to treat viral myocarditis.Qing Re Yang Xin granule has significant efficacy in clinical, but little studied were reported. At present, there are many pharmacological effects and clinical applications investigations reported about Qing Re Yang Xin granule, however, its pharmacokinetic characteristics of the study is relatively scarce. This article attempts to summarize our laboratory group’s early work and then investigate the pharmacokinetic characteristics of Qing Re Yang Xin granule on the basis of literature reported, in order to provide important and necessary information for clinical treatment, follow-up researches and drug development.To develop a LC-MS method for the determination of chlorogenic acid, caffeic acid, glycyrrhetinic acid, diosgenin and oxymatrine in Qing Re Yang Xin granule. To measure the content of the target sample by LC-MS method. Chlorogenic acid, caffeic acid, glycyrrhetinic acid, diosgenin and oxymatrine were all analyzed exactly. The linear ranges were 11.60-2970 (r =0.9986),3.05-780 (r=0.9958),1.10-282 (r=0.9991),3.63-930 (r=0.9931),0.47-120 μg·L-1 (r=0.9977), respectively. A sentive, accuracy and suitable LC-MS method has been developed, and the method can be applied for the determination of chlorogenic acid, caffeic acid, glycyrrhetinic acid, diosgenin and oxymatrine in Qing Re Yang Xin granule.To study the protein binding rate of chlorogenic acid in the plasma of rats, Beagle dogs and humans. Equilibrium dialysis method was carried out to determine the plasma protein binding rates in different species HPLC was employed to determine the concentration of chlorogenic acid inside or outside of the dialysis membrane and then protein binding rates were calculated. The plasma protein binding rates of chlorogenic acid at low, middle and high concentrations in different species were as follows, the plasma protein binding rates were 45.4±2.7%,47.7±3.0%, 45.8±1.6% in rats,40.3±2.1%,42.6±1.8%,42.9±2.3% in Beagle dogs, and 54.3±2.0%, 50.2±2.5%,52.1±3.1% in humans respectively. The protein binding rates of chlorogenic acid were of middle strength, which in humans, rats and Beagle dogs plasma were decreased in the following order:humans plasma> rats plasma> Beagle dogs plasma.To establish a LC-MS/MS method for the determination of caffeic acid, chlorogenic acid in rat plasma and its application to rats. Six Sprague-Dawley rats were i.g. administrated 2 g-kg"1 of Qing Re Yang Xin granule. Drug plasma concentration was determined by LC-MS/MS using ferulic acid as an internal standard. The pharmacokinetic parameters were calculated by DAS 1.0. The linear concentration ranges of the calibration curves for caffeic acid and chlorogenic acid were 25-800 ng·mL-1 (r=0.9965) and 11.25-1440 ng·mL-1 (r=0.9949), respectively. The inner and inter-days relative standard deviations were both less than 9.8%, indicating legitimate precise and accuracy to the requirement of biological sample analysis. For caffeic acid, the pharmacokinetic parameter T1/2β, AUC0-t and Cmax were (180.42±25.54) min, (155397.53±3059.14) ng·min·mL-1 and (729.43±24.56) ng·mL-1, respectively. For chlorogenic acid, the pharmacokinetic parameter T1/2β, AUC0-t and Cmax were (115.94±16.12) min, (191710.99±7263.26) ng·min·mL-1 and (1110.32±15.33) ng·mL-1, respectively. The assay method is proved to be sensitive, accurate and convenient. It can be applied to the pharmacokinetic study of caffeic acid and chlorogenic acid.To observe the influence of Qing Re Yang Xin granule on activities of cytochrome P450 by Cocktail Probe Drugs in rats. Use tolbutamide, chlorzoxazone, theophylline, omeprazole and dextromethorphan as the probe drugs. The five probe drugs were simultsneously given to rats in experimental group and control group. The plasma concentrations of the five probe drugs were determination by LC-MS/MS and their corresponding pharmacokinetic parameters were calculated. There are some difference between the five probe drugs in plasma concentrations and the corresponding pharmacokinetic parameters in rats after intragastric administration of Qing Re Yang Xin granule 10 d. The metabolism of tolbutamide and theophylline was accelerated, and there was no significant difference in the metabolism of omeprazole, chlorzoxazone and dextromethorphan. Qing Re Yang Xin granule can induce CYP2C9, CYP1A2 activity significantly, while no significant influence on the activity of CYP2E1, CYP2C19 and CYP2D6. |
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