| Objective:This study established a preliminary evaluation system for the classification of traditional Chinese medicine biopharmaceutics by computer simulation and experimental verification.The Chinese medicine monomers of ginsenoside Rb1,ginsenoside Rbl,notoginsenoside R1,mogroside V,ziyuglycoside I,glycyrrhizic acid,and ciwujianoside B,anemoside B4,and pseudoprotodiosin were selected as model drugs.its permeability and transport mechanism and to perform BCS classification,investigate the BCS classification and mechanism of transport,and explore the relationship between the saponin structure and the BCS category,and it provided a theoretical basis for the construction of the evaluation system of Chinese traditional medicine biopharmaceuticals and the research on the dosage forms of model drugs.Methods:First,the ADME QSAR model in StarDrop software was used to predict the dissolution characteristics,intestinal absorption properties and the absorption of P-glycoprotein(P-gp),and further use Discovery studio software to further predict the solubility and intestinal absorption properties of model drugs.The solubility of the model drug in different media was measured with reference to the shake flask method and the test method in the Chinese Pharmacopoeia 2015.The ratio(DO)of the maximum dose and solubility of the model drug was used to determine the dissolution.Sex size.The Caco-2 monolayer membrane was used to explore the intestinal absorption mechanism of the drugs.The cytotoxic effect of the drugs on Caco-2 cells were examined by MTT assay,and high,medium and low concentrations were selected for transport experiments.The apparent permeability coefficient(Papp)was calculated to determine its permeability.The effects of time,concentration and P-glycoprotein on drug transport rate were further investigated.The efflux coefficient(ER)was calculated to analyze the transport mechanism.Results:The D0 values of ginsenoside Rbl,ginsenoside Rgl,mogroside V,ziyuglycoside I,ciwujianoside B,anemoside B4,pseudoprotodiosin in pH 1.2,4.0,6.8 phosphate buffer and water were all less than 1 and were highly soluble drugs.The DO values of notoginsenoside R1,glycyrrhizic acid were greater than 1 for low solubility drugs.In the AP to BL transport experiment,the Papp of ginsenoside Rb1 was 7.59×10-6?12.50×10-6cm· s-1;the Papp of ginsenoside Rgl was 1.19×10-6?4.17×10-6 cm·s-1;the Papp of notoginsenoside R1 was 6.98×10-6?10.04×10-6cm·s-1;the Papp of mogroside V was 9.42×10-6?11.16×10-6cm·s-1;the Papp of ziyuglycoside I was 1.12×10-6?3.23×10-6cm·s-1;the Papp of glycyrrhizic acid was 0.09×10-6?0.30×10-6cm·s-1;the Papp of ciwujianoside B was 1.19×10-6?1.53×10-6cm·s-1;the Papp of anemoside B4 was 3.57×10-6?8.04×10-6cm·s-1;the Papp of pseudoprotodiosin was 3.125×10-6?10.459×10-6cm·s-1,all were low permeability drugs.In the three concentrations of high,medium and low,the ER values of ginsenoside Rb1 were 0.94,0.86,and 1.23;the ER values of ginsenoside Rgl were 1.12,0.84,and 0.86,respectively;the ER values of notoginsenoside R1 were 0.94,0.88,1.04;the ER values of mogroside V were 0.59,0.80,1.00;the ER values of ziyuglycoside I were 1.50,6.00,6.00;the ER values of glycyrrhizic acid were 1.47,5.44,1.15;the ER values of ciwujianoside B were 1.28,2.59,and 2.26,respectively;the ER values of anemoside B4 were 1.63,1.68,and 1.06,respectively;the ER values of pseudoprotodiosin were 1.48,1.34,1.01.With the addition of P-gp inhibitor verapamil,the transport rates of mogroside V,ziyuglycoside I,glycyrrhizic acid,ciwujianoside B,anemoside B4 and pseudoprotodiosin were all increased significantly,and P was less than 0.05,indicating that all the six drugs were P-gp substrates.The solubility results predicted by StarDrop model were somewhat different from the actual results.The predicted results of pentacyclic triterpenoid saponins were all substrates of P-gp,which is the same as the experimental results.The dissolution results predicted by Discovery Studio software models were different from the actual results.The permeability results predicted by StarDrop and Discovery Studio were all low-permeability drugs,which were consistent with the experimental results.Conclusion:Ginsenoside Rbl,ginsenoside Rg1,mogroside V,ziyuglycoside ?,ciwujianoside B,anemoside B4 and pseudoprotodiosin are BCS ? drugs,Notoginsenoside R1,glycyrrhizic acid are BCS IV drugs.Tetracyclic triterpene saponins:ginsenoside Rbl,ginsenoside Rgl,and notoginsenoside R1 are mainly passively transported and are all not the substrates of P-gp;mogroside V is mainly passively transported,and its transport is regulated by P-gp.Pentacyclic triterpene saponins:ziyuglycoside ?,glycyrrhizic acid,ciwujianoside B,anemoside B4 are mainly active transporters and all of them are the substrates of P-gp.Steroidal saponins:pseudoprotodiosin exists in both active and passive transport modes and is the substrate of P-gp.The difference in aglycon structure is the reason for the difference in the absorption mechanism between the tetracyclic triterpene saponins and the pentacyclic triterpene saponins.StarDrop software can be used to predict whether pentacyclic triterpenoid saponins are P-gp substrates.StarDrop software and Discovery studio software are not suitable for the determination of the solubility of saponins,and both softwares can be used to predict the intestinal absorption properties of saponins. |
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