磷酸西他列汀在大鼠体内的药代动力学研究

Pharmacokinetics study of sitagliptin phosphate in SD rats

目的:建立超高效液相色谱-电喷雾离子源-串联三重四极杆质谱(UHPLC-ESI-MS/MS)方法测定大鼠血浆中磷酸西他列汀的含量,研究磷酸西他列汀经尾静脉单次给药后在SD大鼠体内的药代动力学过程。方法:18只SD大鼠分为3组,分别单次给予9,3,1 mg.kg-1磷酸西他列汀,按照不同时间点于眼后静脉丛采血。液质联用法测定血药浓度。质谱采用正离子和选择反应监测(SRM)模式,用于定量分析的离子分别为磷酸西他列汀m/z 408.0→235.0和内标氟西汀m/z 310.0→148.0。根据非房室统计矩模型用WinNolin软件进行曲线拟合并计算药代动力学参数。结果:大鼠分别尾静脉单次注射高、中、低剂量(93,和1 mg.kg-1)药物后,血药浓度-时间曲线下面积(AUCINF)分别为(5 154.82±637.37)(,1 729.30±290.76)和(589.39±66.92)h.ng.mL-1,剂量之比为9∶3∶1,对应的AUC比值为8.75∶2.93∶1,与给药剂量呈线性正相关性;统计结果表明3个剂量组的AUC有显著性差异t,1/2,Vz,CL,MRTlast与给药剂量无关。结论:所建立的UHPLC-MS/MS测定方法准确可靠,简便灵敏,可用于磷酸西他列汀药代动力学和生物等效性研究,同时也为临床研究提供参考。在本试验的剂量范围内(1～9 mg.kg-1),磷酸西他列汀在SD大鼠体内符合线性药代动力学特征。

Objective： To establish a model of UHPLC-ESI-MS/MS method to determine sitagliptin phosphate in plasma of SD rats,and investigate the pharmacokinetics of sitagliptin phosphate in SD rats.Methods： A total of 18 SD rats were divided into 3 groups,and treated with a single intravenous injection of 9,3 or 1 mg·kg-1 sitagliptin phosphate respectively for evaluating the pharmacokinetics.At various time points,blood was taken from posterior venous plexus,the plasma concentration was determined,and the concentration and time curve was plotted.In the method of UHPLC-ESI-MS/MS,electrospray ionization source was used as detector and operated in the positive ion mode.In selected reaction monitoring（SRM） mode,the ion combinations of m/z 408.0→235.0 and m/z 310.0→148.0 were used to qualify sitagliptin phosphate and the internal standard（Fluoxetine）,respectively.The pharmacokinetics process fitted with the non-compartment model by WinNolin software.Results： The main pharmacokinetic parameter AUCINF was（5 154.82±637.37）,（1 729.30±290.76） and（589.39±66.92） h·ng·mL-1,respectively,after intravenous injection of 9,3 and 1 mg·kg-1.A linear correlation was observed between the dose（ratio 9∶3∶1） and AUCINF（ratio 8.75∶2.93∶1）.The statistical analysis showed that the values of AUC at 3 doses were significantly different;the values of t1/2,Vz,CL and MRTlast were not affected in the dose range in SD rats.Conclusion： The established UHPLC-ESI-MS/MS method is accuracy,sensitive and convenient.It is suitable for non-clinical investigation of the pharmacokinetics and bioequiavailability of sitagliptin phosphate,and also provides a reference for clinical study.Sitagliptin phosphate exhibits linear pharmacokinetics in the dose range of 1~9 mg·kg-1 in SD rats.