Investigation On The Interactions Between Multi-constituents In Shexiang Baoxin Pill Based On CYP3A4 Metabolism

Shexiang Baoxin pill is a presentive Chinese formula for the treatment of coronary heart disease and is widely used in clinical nowadays. The present research investigated the ineractions between the main bioactive and tocxic compound cinobufagin and other 14 main plasma absorbed compounds of Shexiang Baoxin Pill in human livermicrosomes in vitro to presume the possible reason and mechanism that inhibit CB metabolism. Then we compared the pharmacokinetic parametes of the two groups that orally administrated CB and the same dose of CB contained Shexiang Baoxin Pill in rat plasma to test and verify the inhibition of CB metabolism. The specific aim of this study is to clarify the metabolic behavior of CB in Shexiang Baoxin pill and explain the interactions exsited in Shexiang Baoxin pill in vitro and in vivo.14 main plasma absorbed compounds in Shexiang Baoxin pill including ursodeoxycholic acid, chenodeoxycholic acid, hyodeoxycholic acid, deoxycholic acid, ginsenoside Rb1, ginsenoside Rb2, ginsenoside Re, bufalin, resibufagenin, benzyl benzoate, borneol and isoborneol, muscone, protopanoxadiol (PPD) and protopanaxatriol (PPT) were screened to investigate the inhibition of these compounds exerted on CYP3A4 catalyzed CB hydroxylation in human livermicrosomes. The results showed that bufalin, resibufagenin, muscone, PPD and PPT could competitively inhibit CB metabolism and prolong the half elimination time of CB.Furthermore, the concentration of CB in Shexiang Baoxin pill was determined and the difference of metabolic stability of CB alone and CB in Shexiang Baoxin pill in human livermicrosomes were investigated. Finally, we investigated the pharmacokinetic behavior of CB in CB group and Shexiang Baoxin pill group in rat plama by calculating the PK parametes. The results showed that the value of Cmax, AUC, AUMC, Tmax, t1/2 and MRT in Shexiang Baoxin pill group were higher than those in CB group.The present study provides the experimental data for the metabolic mechanism of CB in Shexiang Baoxin pill both in vitro and in vivo. These data may also provide theoretical support for the clinical use of Shexiang Baoxin pill.