Study On The Effect Of Low-Molecular-Weight Heparin Calcium On Pharmacokinetics Of Breviscapine Injection At Different Doses In Rats

This research studied the pharmacokinetics of Breviscapine combined with low molecular weight heparin (LMWH), which were widely used in clinical treatment of cardiovascular and cerebrovascular disease. By observing the impact LMWH on the pharmacokinetics of Breviscapine at different in rats, this study proved up the mechanism of Breviscapine combined with LMWH from the pharmacokinetic perspective, which provided theoretical basis for preventation ADR of the Breviscapine combined with LMWH and for design of rational dosage regimen and provided a theoretical foundation for future studies of other drug interaction with Traditional Chinese Medicine(TCM) to reduce the ADR rate of Chinese medicine injection. Simultaneously, this paper studied the distribution of the breviscapine to saliva, which would provide reference for Saliva Therapeutic Drug Monitoring(STDM) of TCM.The establishment of a micro-sample determination of Breviscapine was also applied to plasma samples after the screening of sample processing methods and chromatography condition. The method was high sensitivity and selectivity which was fit for the requirements of this study.Plasma samples were collected after intravenous injection at high, medium and low-dose of Breviscapine in rats. Quantification of Breviscapine in plasma samples were determined after processed. 3P97 was used for statistical processing to determine pharmacokinetic parameters which were as follows: t1/2= 4.99min, AUC = 554.69ug?min?mL-1, Vc = 81.24mL?kg-1, CL =0.023mL?min-1; t1/2 = 5.29min, AUC = 1244.33 ug?min?mL-1, Vc = 105.50 mL?kg-1, CL=0.018 mL?min-1; t1/2=5.64min, AUC=2700.38ug?min?mL-1, Vc= 113.78 mL?kg-1, CL = 0.019 mL?min-1. Plasma protein binding rate of Breviscapine were determined by ultrafiltration method at high, medium and low-dose which were as follows: 0.957±0.022, 0.939±0.016, 0.9385±0.018. Pharmacokinetic parameters of Breviscapine combined with LMWH were as follows: t1/2=6.38min, AUC=632.24ug?min?mL-1, Vc=102.81mL?kg-1, CL=0.012mL?min-1; t1/2 = 6.66min, AUC = 1352.39 ug?min?mL-1, Vc = 81.40 mL?kg-1, CL=0.010 mL?min-1; t1/2=10.46min, AUC=3776.35ug?min?mL-1, Vc= 50.78 mL?kg-1, CL = 0.013 mL?min-1. Plasma protein binding rate of Breviscapine combined with LMWH were 0.899±0.009, 0.896±0.011, 0.9029±0.020.The results showed that the ratio of AUC and the dose was costant while t1/2 changed little with the dose increasing, which indicated an elimination process of linear dynamics characteristics at high-, medium and low-dose of Breviscapine in rats, consistant with other reports. Nonlinear dynamics characteristics was presented after administration of Breviscapine combined with LMWH at different doses and distribution of apparent speeded, elimination slowed, suggesting that there may be accumulate of Breviscapine in rats. Plasma protein binding rate, with an average 89.93 percent, didn't change with the dose increased and fell 4 percentage points than that single administration. Free drug concentration playing pharmacological effect would be 2 times of the original concentration, and it might lead to adverse events while enhancing the efficacy, suggesting that regimen should be adjusted after administration of Breviscapine combined with LMWH so that serum concentration in patients achieve and maintain effective therapeutic concentrations in the range.This research tried to study the distribution of Breviscapine in the saliva, the results showed that Breviscapine was not detected in rat saliva using current of the research method, suggesting Breviscapine was not suitable for STDM. But this experiment provided a methodology for study the distribution into saliva of TCM and would help to explore and research of STDM of TCM.