比格犬体内环磷酰胺对白消安药动学及血清GST活性的影响

Effect of Cyclophosphamide on Busulfan Pharmacokinetics and Serum GST Activity in Beagle Dogs

关键词:  环磷酰胺  白消安  药动学  谷胱甘肽巯基转移酶  高效液相色谱法

Key words:  cyclophosphamide  busulfan  pharmacokinetics  glutathione S-transferase  HPLC

摘要:

目的 研究比格犬体内环磷酰胺(cyclophosphamide，Cy)对白消安(busulfan，Bu)的药动学及谷胱甘肽巯基转移酶(glutathione S-transferase，GST)活性影响。方法 取3只比格犬进行双周期交叉试验，设置分组为对照组(单独静脉注射Bu 0.898 mg·kg^–1)和实验组(先连续4 d口服Cy 14.960 mg·kg^–1，然后静脉注射Bu 0.898 mg·kg^–1)，分别在0.083，0.25，0.5，0.75，1，1.5，2，3，4，6，8 h于犬前肢静脉取血2 mL，分离血清，利用高效液相色谱法测定Bu浓度，采用非隔室模型计算药动学参数。利用紫外分光光度法测定并比较对照组和实验组的GST活性。结果 与对照组相比，实验组Bu的MRT减少了25.2%，AUC_0-t减少了44.5%，差异具有统计学意义(P<0.05)。GST活性测定结果表明，实验组各时间点的GST活性比对照组均有提高。结论 预先给予Cy后，GST活性提高，加快Bu消除，降低其血药浓度总体水平。

Abstract:

OBJECTIVE To study the effect of cyclophosphamide (Cy) on busulfan (Bu) pharmacokinetics and glutathione S-transferase (GST) activity. METHODS Three beagle dogs were taken for a two-cycle crossover test,and the groups were divided into the control group and the experimental group.The control group was injected Bu alone (0.898 mg·kg^–1).The experimental group was oral Cy (14.960 mg·kg^–1) for 4 consecutive days,firstly,and then injected Bu (0.898 mg·kg^–1).The 2 mL of blood samples were collected from the forelimb veins of dogs at 0.083,0.25,0.5,0.75,1,1.5,2,3,4,6,8 h.The Bu concentration was determined by HPLC,and the pharmacokinetic parameters were calculated using a non-compartment model.The GST activity of the control group and the experimental group was measured by UV spectrophotometry and compared.RESULTS Compared with the control group,the MRT and AUC_0-t of Bu in the experimental group decreased by 25.2% and 44.5%,respectively.There was a statistically significant difference (P<0.05).The results of GST activity showed that the GST activity in the experimental group was higher than that of the control group at each time points.CONCLUSION GST activity increased after pre-administration of Cy,Bu elimination accelerated,and the overall level of blood concentration decreased.