Pharmacokinetic Parameters Effects Of Aidi Injection On Docetaxel In Rats And Its Partial Mechanism

Objective:To study the effect of Aidi injection on the pharmacokinetic parameters of docetaxel in rats,so as to provide theoretical basis for the clinical use of the two drugs and to explore the possible mechanism.Methods:To establish an efficient,sensitive and rapid liquid chomatography analysis method to determine the concentration of docetaxel in the plasma of rats,and to explore the pharmacokinetics of docetaxel by designing a single dose and multi-dose Aidi injection parameters,and explain the mechanism of metabolic enzyme protein expression.1.Establishment and confirmation of docetaxel UPLC assay in rat plasma:establishment of appropriate chromatographic conditions,treatment of blood samples by methanol precipitation,from the specificity,standard curve and the lower limit of quantification,precision,recovery and stability verify the established method;2.Effects of single dose of Aidi injection on the pharmacokinetic parameters of docetaxel in rats:randomLy selected SD rats were randomLy divided into three groups:Aidi injection high dose group,middle dose group,low dose group and blank control group,in which the high,middle and low dose groups of Aidi injection were given docetaxel by tail vein injection 10min interval after administration of the corresponding dose of Aidi injection.The blank control group was given docetaxel by tail vein injection directly,blood samples were taken at different time points after administration,and the samples were analyzed by pretreatment,and the pharmacokinetic parameters were calculated according to the plasma drug concentration;3.The SD rats were randomLy divided into three groups:Aidi injection high dose group,middle dose group,low dose group and blank control group,including Aidi injection high,medium and low dose group were given the corresponding dose of Aidi injection by tail vein injection for 10 consecutive days,the last time after the end of administration,10min interval given docetaxel by tail vein injection,blank control group before the special treatment has no special treatment,and finally directly given docetaxel by tail vein injection,respectively,in the administration after the different time points to take blood,pretreatment after injection analysis,according to the plasma drug concentration calculated pharmacokinetic parameters;4.The effect of single dose of Aidi injection on the expression of Cyp3a1 protein in rats:SD male rats were randomLy divided into three groups:Aidi injection high dose group,middle dose group,low dose group and blank control group,in which Aidi injection high,medium and low dose groups were given the appropriate dose of Aidi injection by tail vein injection,10min later given docetaxel by tail vein injection,blank control group directly giving docetaxel by tail vein injection,after the end of administration the rats were sacrificed by carotid artery.The liver tissue of rats was taken and stored at-80℃.The expression of Cyp3a1 protein was detected by Western Blot;5.The effect of multi-dose Aidi injection on the expression of Cyp3a1 protein in rats:SD male rats were randomLy divided into three groups:high,medium and low dose of Aidi injection group and control group.After the last administration,the docetaxel was given by tail vein injection at the end of the last administration,and the control group has no special treatment for the same period.Only docetaxel was given by tail vein injection and the carotid artery was sacrificed at the end of the administration.The liver tissue,stored at-80℃refrigerator storage,the use of Western Blot detection of Cyp3a1 protein expression levels.Results:1.Establishment and confirmation of docetaxel UPLC assay in rat plasma:the retention time of docetaxel and internal standard paclitaxel was 10.45 min and7.83 min,respectively,and standard curve line of docetaxel was Y=0.1018X+0.0028,R²=0.9996,the linear relationship was good at 0.05¹0μg/mL,and the intra-day and inter-day precision were less than 15%,the lower limit of quantification of DTX in rat plasma（S/N=10）was 0.05μg/mL,the recovery rate is higher than 85%,and the sample is stable at-80℃and room temperature for 24 hours;2.The effect of single dose of Aidi injection on the pharmacokinetic parameters of docetaxel in rats:Compared with the blank control group,the t_1/2/2 of the high dose group was significantly prolonged,and the C_maxax of the middle dose group was significantly and the other parameters were not statistically significant;3.The effect of multi-dose Aidi injection on the pharmacokinetic parameters of docetaxel in rats:Compared with the blank control group,the Vd and t_1/2/2 of the high dose group were significantly decreased,In the middle dose group,t_1/2,AUC_0-∞and Vd were significantly decreased,CL was significantly increased,and the other parameters were not statistically significant;4.The effect of single dose of Aidi injection on the expression of Cyp3a1 protein in rats:Compared with the control group,the gray values of the other three groups were not significantly different;5.The effect of multi-dose Aidi injection on the expression of Cyp3a1 protein in rats:Compared with the control group,the gray values of the other three groups were not significantly different.Conclusion:The UPLC method established in this study can be used quickly and reliably to determine the concentration of docetaxel in rat plasma.After a single dose of high-dose Aidi injection,it may have a slight effect on the elimination of docetaxel in rats;In the middle dose of Aidi injection,the clearance of docetaxel in rats was accelerated,the high-dose of Aidi injection also accelerate the clearance of docetaxel;Single dose and multi-dose Aidi injection had no significant effect on the expression of Cyp3a1 protein.At present,it was not possible to explain the expression level of Cyp3a1 protein,and further experiments were needed to explore the mechanism of Aidi injection influence the clearance of docetaxel in rats.