The effects of Xiao-Ai-Ping injection on the pharmacokinetics by docetaxel in vivo and CYP450 enzyme activity in vitro of rats
Objective To explore the effects of Xiao-Ai-Ping injection(XAP)on the pharmacokinetics of docetaxel(DOC)in vivo and the activity of human cytochrome P450(CYP450)enzyme in vitro of rats.Methods Twenty-four male SD rats were randomly divided into four groups:DOC control group(Group A),XAP+DOC group(Group B),midazolam(MDZ)control group(Group C)and XAP+MDZ group(Group D)for in vivo research.Ultra high performance liquid chromatography tandem mass spectrometry was used to detect the concentration of DOC/MDZ in rat serum at 5,10,20,30 min and 1,2,3,4,6,8,12,24 h after administration,and the pharmacokinetic parameters was calculated.A recombinant human cytochrome P450 enzyme 3A4(CYP3A4)was used for in vitro study.A study was conducted on the in vitro reaction system of CYP3A4.Human liver microsomes was prepared.The inhibitory effect of XAP on CYP450 activity was investigated using MDZ as the substrate,and the effect of XAP on DOC metabolism was investigated.Results In vivo pharmacokinetic results showed that XAP could increase the Cmax and AUC0 → t of DOC by 150%(P<0.01)and 60%(P<0.05),respectively.The t1/2 and MRT values were(4.24±1.78)h and(3.92±1.14)h,respectively,which were significantly prolonged compared to the DOC control group.XAP could prolong the elimination half-life of MDZ by t1/2 to(0.962±0.19)h,MRT to(1.008±0.13)h,and AUC0→∞ to(1510.078±242.11)ng·h/ml.Both were significantly higher than those in MDZ control group(P<0.05).The in vitro inhibition experiment using MDZ as the substrate showed that XAP(10-100 mg/ml)and C21 total steroid extract(10-50 μg/ml),had a significant inhibitory effect on the activity of human liver microsomal CYP3A4.Conclusion After combined use of XAP and DOC,the blood concentration of DOC increases,and multiple pharmacokinetic parameters of DOC show significant changes.XAP has an inhibitory effect on the elimination of DOC,and this effect may be caused by the inhibition of CYP3A4.
TumorXiao-Ai-Ping injectionDocetaxelCytochrome P450Drug(traditional Chinese medicine)-drug interactionPharmacokineticsCytochrome P450 enzyme 3A4
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