Study On The Compatible Mechanism Of Jiegeng Decotion Based On The Pharmacokinetics

This research was financially supported by National Natural Science Foundation of China Study on the compatible mechanism of Jiegeng Decotion based on multicomponents integrated features of TCM (81001499).Jiegeng decotion (JD) is composed of platycodon (Jiegeng, JG) and licorice (Gancao, GC) with the weight ratio of1:2. This herb-pairs were firstly mentioned in Shanghan Lun, a medical classic written by the famous Chinese physician Zhongjing Zhang (150-219A.D. in Eastern Han Dynasty). In clinical applications, JD has been used as the basic formula to treat sore throat frequently, thus most other formulas which have the same treatment are formed. Platycodon is bitter in taste, no stimulation, which has the effects of facilitating lung, relieving sore-throat, expelling phlegm and apocenosising. Licorice is sweet and insipid in taste, which could invigorate the spleen, benefit vital energy, expel phlegm to arrest coughing, clear away the heat-evil to expel superficial evils, prioritize pain and coordinate the drug actions of a prescription. The combination of platycodon and licorice improved the curative effect of Fei Yong (lung abscess). From the perspective of modern medicine, the main active ingredients of Jiegeng decotion were platycodin and glycyrrhizin which play a part in anti-inflammatory and expelling phlegm.On the basis of literature research, this study researched the in vivo interaction of the active ingredients in Jiegeng decotion systematically by pharmacokinetic methods to discuss the compatibility mechanism of Jiegeng-Gancao herb pair (JGHP). The detection method of Platycodin D, glycyrrhizic acid, glycyrrhetinic acid and liquiritin et cetera were developed in this study. The in vivo pharmacokinetic diversity of these components before and after the combination of Radix Platycodi and Radix Glycyrrhizae were compared, and both the absorption and metabolism of the active ingredients have been researched to explain the possible reasons for the pharmacokinetic changes.Fingerprintings of active ingredient in JD, JE and GE were developed, and the LC-MS/MS method for in vivo quantitative analysis was developed and validated.80components were preliminarily identified from JD,19components were derived from platycodon and61were derived from licorice. Chemical analysis in vitro experiments has showed that the structure and content of the main active ingredient did not change significantly by the compatibility of platycodon and licorice.Pharmacokinetic studies showed that the AUC(0-t) of platycodin D was increased from (89.0±45.4μg·L-1·h) to (540.21±222.15μg·L-1·h) after the combination of platycodon and licorice, the AUC(0-t) of deapio-platycodin D was also increased from (81.3±27.8u.g·L-1·h) to (181.3±73.5μg·L-1·h). The concentration of platycodin D2in rat plasma samples after oral administration of JE was below the lower limit of quantitation (LLOQ), but the concentration of the samples after oral administration of JD in8hours could be quantified. The result indicated that the AUC(0-t) of platycodin D2increased from0to (36.3±11.0μg·L-1·h). The results indicated that the relative bioavailability of oral grandiflorum saponins could be significantly improved by licorice. The AUC(0-t) of glycyrrhizic acid, glycyrrhetinic acid, liquiritin and isoliquiritin were respectively increased from (13531±4038μg·L-1·h) to (41241±10290μg-·L-1·h),(40354±9018μg·L-1·h) to (117530±20640μg·L-1·h),(302±58.1μg·L-1·h) to (1105±270μg·L-1·h), and (75.3±17.6μg·L-1·h) to (136±36.5μg·L-1·-h). The AUC(0-t) of liquiritigenin and isoliquiritigenin were respectively decrease from (533±191μg·L-1·h) to (304±59.1μg·L-1·h), and (202±54.4μg·L-1·h) to (120±31.5μg·L-1·h). The relative bioavailability of oral licorice flavonoids and saponins could be improved by platycodon generally. The results of pharmacokinetic were basically consistent with the anti-inflammatory studies, which indicated that the herb-pair has a cooperative synergism effect.The Caco-2cell mono layer model and the metabolism model of rat fecal lysate were studied in the research. The result of Caco-2cell monolayer model showed that the Papp of the main active ingredients in JD, JE and GE were basically the same,(P>0.05) which indicated that the absorption of the active ingredients was not affected by the compatibility of platycodon and licorice. The in vitro metabolism study by rat fecal lysate indicated that the grandiflorum saponins, licorice saponins and flavonoid glycosides were influenced (deglycosylation) by the metabolizing enzymes such as β-D-glucosidase enzyme. The metabolism of active ingredients both in platycodon and licorice were competitively inhibited by the compatibility of the herb-pair. This could be a major factor to improve the bioavailability of the active ingredients in JD.