熊果酸及其氨基酸酯前体药物在大鼠体内的药动学研究  

Pharmacokinetic study of ursolic acid and its amino acid ester prodrugs in rats

作　　者：赵婷婷 付宇含 秦紫宸 宁亚楠 郭夫江[1] 李医明[1] ZHAO Tingting;FU Yuhan;QIN Zichen;NING Yanan;GUO Fujiang;LI Yiming(School of Chinese Herbal Medicine,Shanghai University of Traditional Chinese Medicine,Shanghai 201203,China;School of Pharmacy,Shanghai University of Medicine&Health Sciences,Shanghai 201203,China)

机构地区：[1]上海中医药大学中药学院,上海201203 [2]上海健康医学院药学院,上海201203

出　　处：《沈阳药科大学学报》2024年第6期734-741,共8页Journal of Shenyang Pharmaceutical University

摘　　要：目的 建立测定大鼠血浆中熊果酸浓度的超高效液相色谱串联质谱(UPLC-MS/MS)分析方法,探讨熊果酸及其氨基酸酯前体药物在大鼠体内的药动学变化。方法 取雄性大鼠,经口给药70 mg·kg^(-1)(以熊果酸含量计)的熊果酸原料药,熊果酸-维生素E琥珀酸聚乙二醇酯混合液,熊果酸苯丙氨酸肌氨酸酯盐酸盐-维生素E琥珀酸聚乙二醇酯溶液。采用沉淀蛋白法处理血浆样品,以塞来昔布作为内标,色谱柱为Acquity UPLC~? BEH C18(50 mm×2.1 mm, 1.7μm)柱,流动相为体积分数0.025%氨水乙腈-10 mmol·L^(-1)乙酸铵-体积分数0.1%氨水溶液(体积比70∶30),流速0.4 mL·min^(-1),采用大气压化学电离源,负离子多反应监测模式扫描。结果 血浆中熊果酸在质量浓度100~10 000μg·L^(-1)内线性良好。与原料药比较,熊果酸-维生素E琥珀酸聚乙二醇酯混合液组和熊果酸苯丙氨酸肌氨酸酯盐酸盐-维生素E琥珀酸聚乙二醇酯溶液组的熊果酸生物利用度分别提高了8.43倍和19.52倍(P<0.05)。结论 经口给药后熊果酸在大鼠体内的生物利用度较低,前体药物熊果酸苯丙氨酸肌氨酸酯可提高熊果酸的经口给药生物利用度。分析方法符合生物样品的测定要求,适用于大鼠血浆中熊果酸质量浓度的测定。Objective To develop an ultra-performance liquid chromatography tandem mass spectrometry(UPLC-MS/MS)method for the determination of ursolic acid in rat plasma,and to explore the changes in pharmacokinetic of ursolic acid and its derivatives in rats.Methods Male rats were intragastrically given 70 mg·kg^(-1)(measured by ursolic acid content)ursolic acid,ursolic acid-Vitamin E polyethylene glycol succinate(TPGS),ursolic acid phenylalanine sarcosine ester hydrochloride-TPGS.Precipitated protein was used to pretreat plasma samples.Celecoxib was used as an internal standard substance.The determination was performed on Acquity UPLC~?BEH C_(18)(50 mm×2.1 mm,1.7μm)column with mobile phase consisted of 0.025%ammonia acetonitrile-10 mm ammonium acetate 0.1%ammonia solution(V∶V=70∶30)at a flow rate of 0.4 mL·min^(-1).The multiple reaction monitoring mode was performed in negative ion mode with atmospheric pressure chemical ionization source.Results The linear range of ursolic acid in plasma ranged from 100 to 10000μg·L^(-1).Compared with active pharmaceutical ingredient,the bioavailability of ursolic acid in ursolic acid-TPGS group and ursolic acid phenylalanine sarcosine ester hydrochloride-TPGS group were increased by 8.43 times and 19.52 times respectively(P<0.05).Conclusion The oral bioavailability of ursolic acid in rats is low,and the precursor drug ursolic acid phenylalanine sarcosine ester hydrochloride can improve the oral bioavailability of ursolic acid.The method is suitable for the determination of ursolic acid in rat plasma.

关 键 词：熊果酸 氨基酸酯前药 熊果酸苯丙氨酸肌氨酸酯盐酸盐 UPLC-MS/MS 药动学 

分 类 号：R917[医药卫生—药物分析学]