Plasma Pharmacokinetics Of Weichangzi Injection And Thrombus In Beagle Dogs

Ischemic cerebrovascular disease is caused by various causes of cerebral vascular blockage, resulting in cerebral vascular dysfunction, causing related symptoms. It has the characteristics of high incidence rate, high morbidity rate, high recurrence rate and high mortality rate, which is a serious hazard to human health and life. In clinical, Kudiezi injection (KDZ) or Xueshuantong (XST) are usually used to treat ischemic cerebrovascular disease, and clinical research showed that the treatment effect is better after combined application. Whether the metabolite of their main ingredients interacted after taking the medicine simultaneously was reported insufficient by far. This paper established a pretreatment method for dealing with 8 active components of KDZ and 4 active components of XST in beagle dog plasma. Based on the above research, the metabolism process of two medicines combination in beagle dogs were preliminarily discussed according to the pharmacokinetic parameters. The pharmacokinetics of the main active components of KDZ and XST in the beagle dogs were studied after combined administration of KDZ and XST. By comparing the differences of pharmacokinetic parameters, the purpose of the study is to explore the interactions between KDZ and XST, and to lay the foundation for their rational combination application in clinical. The main research contents and results are as follows.1. Rapid determination of 10 active components in Kudiezi injection by UPLC-ESI-MS/MSA rapid and sensitive method was developed to simultaneously determine 10 active components in Kudiezi injection by UPLC-ESI-MS/MS. The UPLC separation was performed on a (2.1 mm×50 mm,1.7μm) Waters BEH C18 column with the mixture of acetonitrile-0.5% formic acid at a flow rate of 0.4mL·min-1, the column temperature was 40℃. Multiple reaction monitoring was applied to the quantitative analysis with ESI negative mode. The 10 active components were separated completly within 5 min. The regression equations showed good linear relationships within their respective linear ranges. The established analysis method was confirmed, and the results satisfied with the requirement of related regulations.2. A quantitative method was developed for the simultaneous determination of 8 active components of Kudiezi injection in beagle dog plasmaA method for simultaneous determination of 8 active components of Kudiezi injection in beagle dog plasma was established by using UPLC-MS/MS. Internal standard is puerarin and a protein precipitation method using 2 times of acetonitrile was developed to treat the samples of plasma. The UPLC separation was performed on a (2.1 mm×50 mm,1.7μ,) Waters BEH C18 column with the mixture of acetonitrile-0.5% formic acid at a flow rate of 0.4 mL·min-1. Multiple reaction monitoring was applied to the quantitative analysis with ESI negative mode. And the established analysis method was comprehensive confirmed. The results demonstrated that the method is specific, high sensitivity, and can be used to research pharmacokinetic study of 8 active components of Kudiezi injection in beagle dog plasma.3. A quantitative method was developed for the simultaneous determination of 4 active components of Xueshuantong in beagle dog plasmaA method for simultaneous determination of 4 active components of Xueshuantong in beagle dog plasma was established by using UPLC-MS/MS. Internal standard is digoxin and plasma samples were treated by 250μL acetonitrile protein precipitation.The analysis was performed on a (2.1 mm×50 mm,1.7μm) Waters BEH C18 column with the mixture of acetonitrile-water at a flow rate of 0.4 mL·min-1. Multiple reaction monitoring was applied to the quantitative analysis with ESI positive mode. The established analysis method was comprehensive verified. The results showed that the method is rapid, high sensitivity, and can be used to research pharmacokinetic study of 4 active components of Xueshuantong in beagle dog plasma.4. Comparative pharmacokinetic study on Kudiezi injection and Kudiezi injection combined with Xueshuantong in beagle dog plasmaThe healthy adult beagle dogs were used as experimental objects and administrated by intravenous infusion. The above established method was used to study the pharmacokinetics of a single drug delivery group (KDZ) and the compatibility group (KDZ-XST) in beagle dogs. The pharmacokinetic parameters were calculated by Phoenix winnonlin Ver.6.3 software, and were comparative analyzed using the statistical software SPSS 20.0. Based on the above results, the metabolism process of the main active components of Kudiezi injection in beagle dogs were preliminarily discussed after combined use KDZ and XST. The results indicated that the pharmacokinetic parameters of organic acids, flavonoids and sesquiterpene lactone in Kudiezi injection have significant difference on statistics. The results were as follows:Favonoids:AUC and MRT of Luteolin-7-O-β-D-glucoside and apigenin glucoside-7-O-β-D-glucoside were significantly decreased. The Cmax of Luteolin-7-O-β-D-glucoside was dramatically decreased, the t1/2 of apigenin glucoside-7-O-β-D-glucoside was significantly decreased.Sesquiterpene Lactones:MRT and t1/2 of Ixerin Z and 11,13α-dihydroixerin Z were significantly reduced.Chlorogenic acid:the t1/2 of cryptochlorogenic was significantly prolonged and Vd increased.5. Comparative pharmacokinetic study on Xueshuantong and Kudiezi injection combined with Xueshuantong in beagle dog plasmaThe healthy adult beagle dogs were used as experimental objects and administrated by intravenous infusion. The above estabolished method was used to study the pharmacokinetics of a single drug delivery group (XST) and the compatibility group (KDZ-XST) in beagle dogs. The results showed that the AUC of notoginseng saponin R1, ginsenoside Rd and Re were significantly increased and CL decreased. The Cmax of notoginseng saponin R1, ginsenoside Re, Rgland Rd were obviously raised and Vd decreased.