大鼠体内恩丹西酮与氯丙嗪的药动学相互作用研究

 目的建立同时测定大鼠血浆中恩丹西酮、氯丙嗪的HPLC-UV分析方法,探索恩丹西酮与氯丙嗪在大鼠体内药动学的相互作用,并进行高蛋白食物对2种药物药动学影响的研究。方法以替米沙坦为内标,乙酸乙酯提取,HPLC-UV分离、分析。色谱系统:C₈柱(4.6mm×250mm,5μm),甲醇-水(70:30)为流动相,流速1.0mL·min^-1,柱温30℃。以大鼠为研究对象,分别在禁食和服用高蛋白食物状态下给以恩丹西酮、氯丙嗪或联合使用2种药物。用建立的血药浓度测定方法测定,计算其药动学参数并进行t检验。结果联合用药后,恩丹西酮的ρ_max,t_1/2,MRT,AUC_0→t,AUC_0→∞与单独用药时相比显著性增加。氯丙嗪单独用药和联合用药时的ρ_max,t_1/2,MRT,AUC_0→t,AUC_0→∞无显著性差异。高蛋白食物能使恩丹西酮的ρ_max,AUC_0→t,AUC_0→∞明显增加,使氯丙嗪的t_max延长,ρ_max,AUC_0→t,AUC_0→∞降低。结论恩丹西酮和氯丙嗪联合使用时,恩丹西酮的药动学过程会受到显著性影响;食用高蛋白食物后,恩丹西酮和氯丙嗪的药动学参数均会发生明显的改变,应在临床使用中注意这些问题,适当调整药物剂量。

Study on Pharmacokinetic Interaction of ondansetron and Chlorpromazine in Rat

OBJECTIVE To built a sensitive and specific HPLC-UV method for the determination of ondansetron and chlorpromazine simultaneously in rat plasma.METHODS Telmisartan was used as internal standard and the plasma samples were extracted with ethyl acetate.The separation was carried out on a C₈ column(4.6 mm×250 mm,5 μm) using a mobile phase consisting of methanol-water(70∶30) delivered at 1 mL·min^-1.The rats were given with ondansetron,chlorpromazine or ondansetron combined with chlorpromazine respectively after 12 h fasting or feeding with high protein food.The plasma concentration was determinated by the HPLC-UV method and the pharmacokinetic parameters were analyzed.RESULTS The ρ_max,t_1/2,MRT and AUC_0→t and AUC_0→∞ of ondansetron were elevated after combining with chlorpromazine,and the ρ_max,t_1/2,MRT and AUC_0→t,AUC_0→∞ of chlorpromazine had no obviously change.The high protein food increased the ρ_max,AUC_0→t and AUC_0→∞ of the ondansetron and decreased the ρ_max,AUC_0→t and AUC_0→∞ of the chlorpromazine.CONCLUSION When the ondansetron was combined with chlorpromazine,the pharmacokinetics of ondansetron was changed significantly.High protein food can make significant effect on the pharmacokinetic parameters of ondansetron and chlorpromazine.