川续断皂苷乙对氟苯尼考在大鼠体内的药动学影响

Effect of Dipsacoside B on Pharmacokinetics of Florfenicol in Rats

关键词:  川续断皂苷乙  氟苯尼考  大鼠  药动学  细胞色素P450  P-糖蛋白

Key words:  dipsacoside B  florfenicol  rats  pharmacokinetics  CYP450  P-gp

摘要:

研究川续断皂苷乙对氟苯尼考在大鼠体内药动学影响。将24只大鼠(200 g±10 g)随机分成两组,每组12只。试验组连续7 d灌胃川续断皂苷乙(60 mg/kg,1 次/d),对照组给予相同体积的生理盐水,第8天两组各6只大鼠灌服氟苯尼考(30 mg/kg)后按时间点连续采血,采用高效液相色谱法检测氟苯尼考血药浓度,数据采用DAS2.0进行分析。各组剩下的6只处死解剖取肝脏和空肠,荧光定量PCR法和免疫印迹法分别检测组织中CYP1A2、CYP2C11、CYP3A1、 MDR1的mRNA表达水平和蛋白表达水平。结果表明,试验组AUC0-∞、MRT0-∞、T1/2和Cmax与对照组相比显著增加(P<0.05),CL与对照组相比显著降低(P<0.05)；试验组CYP1A2、 CYP2C11在肝脏的mRNA表达水平和MDR1在空肠的mRNA表达水平与对照组相比显著降低(P＜0.05)；试验组大鼠肝脏中CYP1A2和CYP2C11酶表达量以及空肠中P-糖蛋白表达量与对照组相比显著降低(P<0.05)。 结论,川续断皂苷乙连续给药7 d,增加了氟苯尼考在大鼠体内的吸收程度,同时延缓了代谢,可能与川续断皂苷抑制了CYP1A2酶和CYP2C11酶在肝脏的表达和P-糖蛋白在空肠的表达有关。

Abstract:

To study the effect of Dipsacoside B on pharmacokinetics of florfenicol in rats. 24 rats（200 g±10 g） were randomly divided into two groups, experiment group and control group, each group have 12 rats. The rats in experiment group were orally administered with Dipsacoside B (60 mg/kg, 1 t/d) for 7 continuous days, and the same volume of normal saline was given to the control group. The 6 rats in each two groups were continuously sampled by time points on 8d after administration of florfenicol (30 mg/kg), UHPLC method were used for detecting the florfenicol concentration in Plasma of each group, and the data was analyzed by DAS2.0 program. The last 6 rats in each group with no florfenicol were slaughtered by carbondioxide asphyxiation machine. Each liver，jejunum sample was removed quickly, perfused with ice-cold saline to remove blood residue, blotted dry, and stored at -80 oC. Real-time PCR and Western-blot were used to determine the effects on the expression levels of mRNA and protein of CYP1A2 、CYP2C11、CYP3A1 and MDR1 gene in the liver and jejunum samples in each group. The pharmacokinetic parameters of AUC0-∞、MRT0-∞、T1/2 and Cmax in experiment group were increased significantly compare to the control group（P<0.05）, and CL is decreased significantly（P<0.05）. The Real-time PCR results indicated that Rats in experiment group orally administered with Dipsacoside B for 7 continuous days could inhibit the mRNA expression level of CYP1A2 and CYP2C11 in livers (P＜0.05) and MDR1 (P＜0.05) in jejunum .The Western-blot results indicated that Dipsacoside B could decreased the expression level both on CYP1A2 and CYP2C11 in livers and P-gp in jejunum. In conclusion, we suggested that Dipsacoside B affected the pharmacokinetics of florfenicol in rats, this was probably related to the protein expression of CYP1A2 and CYP2C11in liver and MDR1 in jejunum decreased by Dipsacoside B. These ?ndings emphasize that when florfenicol is co-administered with Dipsacoside B, there may be drug-drug interactions, which may increases the prophylactic or therapeutic effectiveness of florfenicol.