Study On The Pharmacokinetics Of Platycodin D

The subject comes from The National Natural Science Foundation of China Based on Chinese medicine multi-component integrated features study compatibility mechanism of Glycyrrhiza and Platycodi (Grant No:81001499).Platycodon is the root of P.grandiflorum(Jacq.)A.DC, which shows the effects of dispersing the lung to resolve phlegm, soothing the throat, and draining the pus.Platycodon contains a variety of ingredients, such as triterpenoids saponins, flavonoids, polysacchari.de, Steroid, aliphatic acid and other ingredients. Pentacyclic triterpenoid saponins compounds were the highest content, which including platycodin A, C, D, D2, D3, among these platycodin D was used as the indicator composition of the quality control in its preparation and herb. Pharmacological studys had proved that Platycodin D has the effect of antiociceptive, improveing the immunogenicity, anti-inflammatory,, lowering cholesterol and other effects, which is according to the effects of Platycodon.The subject systematic studys the pharmacokinetics of the main active ingredient of Platycodin--Platycodin D, and investigates the factors that effect the bioavailability of Platycodin D from the perspective of the absorption and metabolism and so on.Platycodin D plasma concentration was determined by UPLC-MS-MS for the first time. The subject investigated the bioavailability of Platycodin D by rats in vivo pharmacokinetic model. The mentioned method was sensitive, specific and suitable for pharmacokinetics studies on Platycodin D in rat.This subject studys the pharmacokinetic parameters of Platycodin D was initially investigated by in vivo pharmacokinetic model of rats. The parameters from oral aministration study are Tmax 0.69±0.45h,AUC(0～t) 43.15±0.66μg·h-1·mL-1,MRT(0～t) 1.66h±0.67h,CL 236.50±0.59L·h-1·kg-1. The parameters from intravenous administration study are Tmax 0.23±0.21h, AUC(0～t) 88.47±0.18μg·L-1·h-1, MRT(0～t) 1.00±0.22h, CL 0.73±0.24L·h-1·kg-1. The bioavailability of Platycodin D after oral administration is 0.49%.The results from in situ intestinal perfusion model showed that the residue of Platycodin D with different concentrations had little significant differences from that obtained after perfusing via duodenum, jejunum, ileum and colon(P>0.05), which indicated that the absorption of Platycodin D had no difference in different segments of rat intestine. The Peff of different segments is about 5×10-5, which indicated that the absorption of platycodin D is very low. Platycodin D may absorpted by passive diffusion mainly.The Caco-2 cell monolayer transport model was used to study the double transport mechanism of Platycodin D. To explore the factors that effect the absorption of Platycodin D, the drug concentration was determined by using UPLC-MS-MS instrument and the Papp was calculated. The study shows that, the absorption of Platycodin D in Caco-2 cell was related to time, the concentration of drug. After 120 minutes the absorption of Platycodin D by Caco-2 cell was reached a saturated trend. The platycodin D uptaked by Caco-2 cell increased with the increase of the administered concentration, which showed a good linear relationship. In this study, the pH value was set to 6.8, the temperature was set to 37℃. The Papp(AP-BL) was 3.03×10-7cm·s-1, Papp(BL-AP) was 3.30×10-7 cm·s-1, which demonstrated that the membrane permeability of platycodin D is poor, this may be one reason of its low bioavailability. Further experiments showed that after the effect of verapamil, which is P-gp inhibitor, the value of app(AP-BL),Pap(BL-AP)/Papp(AP-BL) decreased but have no signifcances, demonstrated that verapamil cannot effect the transport of platycodin D, showing that Platycodin D is not the substrate of P-gp.The metabolism of flora on different concentrations platycodin D was also study by using rat intestinal flora model, the results shows that the flora has a strong effect on the metabolism of platycodin D, after 12h it was almost degradated completely. The strong intestinal flora metabolism also may be another reason for the low bioavailability of platycodin D.The concentration of platycodin D in.faece and urine at different time periods which was given by oral administration was determine by UPLC-MS-MS. The results showed that prototype drug excretion is rarely, excretion rates were 0.21% and 0.05%, less than 1% of the administered dosage, which confirmed that platycodin D may be extensively metabolized after oral administration...