基于UPLC-MS/MS的新型脂肪酸合成酶抑制剂4k在大鼠体内的药动学研究

Pharmacokinetics study of a new fatty acid synthesis inhibitor 4k in rats by UPLC-MS/MS

关键词:  N-苄基苯胺类  脂肪酸合成酶抑制剂  超高效液相色谱-串联质谱  药动学

Key words:  N-benzylanilines  fatty acid synthase inhibitor  UPLC-MS/MS  pharmacokinetics

摘要:

目的 建立超高效液相色谱-串联质谱法(UPLC-MS/MS)测定大鼠血浆中新型脂肪酸合成酶抑制剂4k的浓度,并研究其在大鼠体内的药动学特征。方法 12只SD大鼠随机分为2组,分别单次尾静脉注射和灌胃给予4k。以三氯生为内标,建立并验证UPLC-MS/MS测定不同时间点大鼠血浆中4k的浓度,用DAS 2.0软件计算药动学参数。结果SD大鼠单次静脉注射后主要药动学参数为T_1/2 (0.54±0.39)h,T_max 0.033 h,C_max (2 730.72±803.13)ng·mL^-1,AUC_0-∞ (577.72± 174.58)ng·mL^-1·h,Vd (1 241.17±657.98)mL·kg^-1,CL (1 882.67±610.03)mL·kg^-1·h^-1,MRT_0-∞ (0.42±0.19)h。由于灌胃给药后,大鼠体内血药浓度低于定量下限,因此无法进行药动学参数计算。结论 本方法简单准确、快速灵敏,适用于大鼠血浆中4k浓度的测定及其药动学研究。

Abstract:

OBJECTIVE To establish a ultra-high performance liquid chromatography-tandem mass spectrometry method (UPLC-MS/MS) to determine the concentration of a new fatty acid synthesis inhibitor 4k in rat plasma, and study on its pharmacokinetic characteristics. Methods Twelve SD rats were randomly divided into two groups, and 4k was given by single intravenous injection and intragastric administration respectively. Using triclosan as the internal standard, the UPLC-MS/MS method was established and verified to determine the concentration of 4k in rat plasma at different time points, and the pharmacokinetic parameters were calculated by DAS 2. 0. Results The main pharmacokinetics parameters of SD rats were as follows:T_1/2 (0.54±0.39)h, T_max 0.033 h, C_max (2 730.72±803.13)ng·mL^-1, AUC_0-∞ (577.72±174.58)ng·mL^-1·h, Vd (1 241.17±657.98)mL·kg^-1, CL (1 882.67±610.03)mL·kg^-1·h^-1, MRT_0-∞ (0.42±0.19)h. After intragastric administration, the blood drug concentration in rats was lower than the lower limit of quantification, so the pharmacokinetic parameters could not be calculated. Conclusion This method is simple, accurate, rapid and sensitive, and suitable for the determination of 4k concentration in rat plasma and its pharmacokinetic study.