Study On Effect Of Ozagrel Sodium On The Pharmacokinetics Of Breviscapine In Rats At Different Doses

This research studied the pharmacokinetics of Breviscapine combined with Ozagrel Sodium, which were widely used in clinical treatment of cardiovascular and cerebrovascular disease. By observing the impact of Breviscapine on the pharmacokinetics and bile,urine excretion process at different doses in rats, this study proved up the mechanism of Breviscapine combined with Ozagrel Sodium from the pharmacokinetic perspective, which provided theoretical basis for preventation ADR of the Breviscapine combined with Ozagrel Sodium and for proved up the mechanism to improve the efficacy of combinayion therapy 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.The establishment of a micro-sample determination of Breviscapine was also applied to biological samples including Plasma samples,bile, Urine 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.Biological samples were collected after intravenous injection at low, medium and high-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=22.149±0.544min, AUC= 341.482±29.251ug-min·mL-1, Vc= 113.755±6.460mL·kg-1, CL= 7.321±0.004mL·min-1. t1/2= 25.095±0.288min, AUC= 769.713±52.284 ug·min·mL-1, Vc=104.509±8.017mL·kg-1, CL= 6.496±0.002 mL·min-1. t1/2=24.846±0.331min, AUC= 1681.521±92.574ug·min·mL-1, Vc= 81.136±14.183 mL·kg-1, CL= 5.947±0.002 mL·min-1. Plasma protein binding rate of Breviscapine were determined by equilibrium dialysis method at high, medium and low-dose which were as follows:0.945±0.019,0.938±0.015,0.947±0.021. Biliary cumulative excretion rate results are as follows:25.416±4.362, 27.669±4.223,29.319±3.021. Urinary cumulative excretion rate results are as follows:4.474±0.992,6.703±1.276,7.832±0.944, Pharmacokinetic parameters of Breviscapine combined with Ozagrel Sodium were as follows:t1/2 = 27.371±1.413min, AUC= 611.344±65.576ug·min·mL-1, Vc= 102.712±15.487mL·kg-1, CL= 4.089±0.002mL-min"1; t1/2= 29.451±1.337min, AUC= 1351.297±94.282 ug·min·mL-1, Vc= 81.394±9.115mL-kg-1,CL= 3.701±0.002mL-min-1; t1/2= 32.652±1.242min, AUC= 3775.361±116.958ug·min·mL"1, Vc= 50.755±6.572 mL·kg-1, CL= 2.648±0.004 mL·min-1. Plasma protein binding rate of Breviscapine combined with Ozagrel Sodium were 0.898±1.264,0.9018±0.020,0.896±0.008; Biliary cumulative excretion rate results are as follows:19.725±2.081,17.239±3.224,16.349±3.128; Urinary cumulative excretion rate results are as follows:12.121±1.179, 10.556±1.451,8.167±1.575.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 Ozagrel Sodium 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 89.881 percent, didn't change with the dose increased and fell about 5 percentage points than that single administration. Free drug concentration playing pharmacological effect would be 1.8 times of the original concentration, which led to significant changes in clinical effect.The speed of biliary excretion more lower and the speed of urine excretion more faster after combination therapy.Overall,the excretion results is slow down. The impact can not be ignored that the change of excretion rate on the efficacy of drugs.It might lead to adverse events while enhancing the efficacy, suggesting that regimen should be adjusted after administration of Breviscapine combined with Ozagrel Sodium so that serum concentration in patients achieve and pay close attention to adverse reaction and maintain safe and effective therapeutic concentrations in the range.