| Objective:Based on the traditional theory of Chinese medicine,Compound danshen dropping pill(CDDP)is a modernized industrialized version of a herbal medicine which is developed by Tasly Group for clinical therapy of cardiovascular diseases.It has become important drug for the treatment of cardiovascular and cerebrovascular diseases since the last ten years and first flagship product of Tasly Group.CDDP,comprised of Salvia miltiorrhiza(Danshen),Panax notoginseng(Sanqi)and Borneolum Syntheticum(borneol),modern researches indicate borneol could play a promoting role to the absorption of other drugs.Currently,the research of rational proportion of borneol in CDDP is unsubstantial,therefore,investigating the rationality of proportion of borneol in CDDP is indispensable.This paper would carry out a study for Fufang Danshen products with different levels of borneol about its constituents absorbed into blood and small intestine and pharmacokinetic process to investigate the rationality of borneol proportion in CDDP for providing a strong support to ensure the safe and effective clinical application.Furthermore,it would lay a solid foundation for the deep research and product second developmentMethods:(1)In this experiment five species of Fufang Danshen preparations which the ratio of principal components and borneol is 10:0,10:0.5,10:0.75,10:1(CDDP),10:1.5,the proportion of borneol is increasing According to the different borneol proportion five species of Fufang Danshen preparations were named after group 10:0,10:0.5,10:0.75,10:1,10:1.5.(2)Based on the application of LC-MS/MS analysis technology,the studies were developed in this paper for constituents absorbed into blood and artificial intestinal juice of CDDP.Also,the linearity,precision,accuracy,recovery rate,stability,repeatability,etc,were investigated for the method.(3)Rat blood samples were collected at a series of time point in 24 and 72 hours for PK maker of Danshen and Sanqi after intragastric administrations which were analyzed after pretreatment by LC-MS/MS,respectively.The pharmacokinetic parameters for the main components were calculated with DAS 2.0 practical pharmacokinetics program to investigate influence of borneol on absorption of Danshen and Sanqi.Result:(1)On the basis of literature investigation and previous research results,we choose tanshinol,protocatechu aldehyde,4-Hydroxy-3-methyloxyphenyl lactic acid,protocatechuic acid,ginsenoside Rbl and ginsenoside Rgl as the index component.(2)In this study,two sensitive,specific and rapid LC-MS/MS methods were established and their specificity,precision,accuracy,extraction rate and stability all meet the requirements of the analysis.The method was successfully applied to pharmacokinetic study for CDDP.(3)The pharmacokinetic results of Danshen reveal there is no significant difference in absorption of protocatechualdehyde tanshinol,4-Hydroxy-3-methyloxyphenyl lactic acid and protocatechuic acid in five groups.For instance in five groups,the AUC0-24h(ng·h/mL)of DSS was 844.57±567.41,780.38±596.50,1285.07±741.42,1172.1 8±453.39,1128.54±695.32;the AUC0-24h(ng·h/m L)of HMPLA was 888.18±229.19,705.20±338.97,1043.10±466.02,1072.57±3 10.34,1085.75±523.05;the AUC0-24h(ng·h/mL)of PCA was 89.69±37.64,94.03±49.77,78.56±42.42,96.82±45.91,78.46±43.07;the AUC0-24h(ng·h/mL)of PAA was 367.1 3±126.94,417.72±108.98,629.29±133.48,489.39±144.43,477.07±238.51.The results indicate borneol do not accelerate absorption of phenolic acids in CDDP.The pharmacokinetic results of Sanqi were as follows,in group 10:0,10:0.5,10:0.75,10:1,10:1.5,the AUC0-72h(ng·h/mL)of Rg1 was 8.80±4.87,8.58±3.47,8.32±2.41,15.27±4.80,14.48±3.98,Tmax was 0.89±0.66,0.26±0.11,0.28±0.08,0.25±0,0.22±0.06;the AUC0-72h(ng·h/mL)of Rb12126.70±1173.11,2092.69±1275.41,1636.59±736.40,3475.55±1501.17,3890.31±2095.39,Tmax was 4.81±2.32,3.75±2.53 3.62±2.04,1.90±2.64,1.37±1.72.2027.23±841.21,1970.72±1021.63,1506.47±185.15,4121.73±980.19,4393.81±2183.07;the Cmax(ng/mL)was 83.68±36.03,70.44±42.88,55.27±4.86,181.74±57.04,1 85.57±84.35;the Tmax was 5.67±1.97,4.83±1.83,3.1 7±2.27,1.13±1.12,0.92±1.06,respectively.(4)Based on the experiments in vitro,compared results of Ka in group 10:0 and 10:1,in ileum,jejunum,duodenumthe,Ka of DSS was 0.0217±0.0048 and 0.01 21±0.0020,0.0221 ± 0.001 7 and 0.01 72± 0.0036,0.0352±0.002 and 0.0186±0.002;Ka of PCA was 0.0052±0.0005 and 0.0055±0.0009,0.0083±0.0005 and 0.0084±0.0022.0.0079±0.0005 and 0.0070±0.0005;Ka of Rg1 was 0.0089±0.0019 and 0.0118±0.0019,0.0064±0.00 and 0.0105±0.0027,0.0198±0.0018 and 0.0151±0.0021;Ka of Rb1 was 0.0017±0.0004 and 0.0020±0.0003,0.0010±0.00 and 0.0022±0.0005,0.0043±0.0003 and 0.0026±0.0005.The results show affect of borneol was different in different parts of small intestine.Conclusion:(1)The established methods were accurate,simple and fast,conforming requirements of method validation.(2)The pharmacokinetic results of Danshen reveal there is no significant difference in absorption of protocatechualdehyde tanshinol,4-Hydroxy-3-methyloxyphenyl lactic acid and protocatechuic acid in five groups.Borneol do not promote absorption of phenolic acids in CDDPs.(3)Borneol promote absorption of Rgl and Rbl in CDDPs,speed up the absorption rate and increase uptake.(4)Based on the experiments in vitro,the absorption tendency of borneol to DSS,Rg1,Rb1 in different positions of the small intestine is different,it is difficult to judge whether the borneol increase the exposed quantity of Rgl and Rbl through increasing intestinal absorption.Therefore,the approach of borneol promoting absorbtion of Rgl and Rbl needs further research. |
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