达立通浸膏中延胡索乙素、川陈皮素和木香烃内酯在大鼠体内的药代动力学及组织分布研究  

Pharmacokinetics and tissue distribution of tetrahydropalmatine,nobiletin,and costunolide in rats after oral administration of Dalitong extract

作　　者：张渊茂 张冉 廖睿伟 陶琳 孟秀秀 徐晨 高芳芳 阿基业[1] 王广基[1] ZHANG Yuanmao;ZHANG Ran;LIAO Ruiwei;TAO Lin;MENG Xiuxiu;XU Chen;GAO Fang-fang;A Jiye;WANG Guangji(Key Laboratory of Drug Metabolism and Pharmacokinetics,China Pharmaceutical University,Nanjing 210009,Jiangsu,China;NanchangHongyiPharmaceuticalCo.,Ltd,Nanchang330006,Jiangxi,China)

机构地区：[1]中国药科大学药物代谢动力学重点实验室,江苏南京210009 [2]南昌弘益药业有限公司,江西南昌330006

出　　处：《中国临床药理学与治疗学》2024年第1期37-51,共15页Chinese Journal of Clinical Pharmacology and Therapeutics

摘　　要：目的:研究达立通浸膏给药后大鼠体内主要药物成分及药代动力学特点。方法:建立同时检测延胡索乙素、川陈皮素和木香烃内酯的超高效液相色谱-串联质谱(UPLC-MS/MS)方法,应用于测定大鼠血浆和组织中药物浓度及药代动力学特征。结果:建立了同时定量测定延胡索乙素、川陈皮素和木香烃内酯方法,单次灌胃给予达立通浸膏后,延胡索乙素、川陈皮素和木香烃内酯可以快速吸收进入体内,在血中峰浓度(C_(max))分别为(13.73±7.50)、(27.01±17.69)、(66.73±29.94)ng/mL,曲线下面积(AUC_(0-t))分别为(80.43±40.03)、(41.30±28.69)、(303.90±136.69)ng·h·mL^(-1),消除半衰期(t_(1/2))分别为(5.82±2.22)、(1.08±0.01)、(4.95±2.53)h。多次给药能明显增加各物质体内暴露水平。各成分在大鼠的主要组织/器官中广泛分布,在胃肠道中暴露水平最高,其次是肝和肾。各成分存在明显的雌雄差异,在雌性大鼠中的暴露量(C_(max)和AUC)均显著高于雄性大鼠(P<0.05)。结论:UPLC-MS/MS测定延胡索乙素、川陈皮素和木香烃内酯的方法准确、灵敏、可靠。达立通浸膏中延胡索乙素、川陈皮素和木香烃内酯可吸收进入血液、广泛分布于体内组织、器官、较快代谢/消除,为达立通浸膏潜在的体内药代标记物。AIM:To investigate the pharmacoki-netic properties of the main active components of Dalitong extract in SD rats after oral administration using UPLC-MS/MS.METHODS:An UPLC-MS/MS method was established to simultaneously detect tetrahydropalmatine,nobiletin and costunolide in the plasma and tissues of SD rats.The method was applied to investigate the pharmacokinetic charac-teristics and tissue distribution.RESULTS:After a single oral administration,the three active compo-nents were rapidly absorbed into the body,with a peak concentration(C_(max))of(13.73±7.50),(27.01±17.69)and(6.73±29.94)ng/mL for tetrahydropal-matine,nobiletin,and costunolide,respectively.The time to reach the peak concentration(T_(max))was(1.40±0.93),(0.63±0.28)and(2.38±8.81)h,re-spectively.The area under the curve(AUC)was(80.43±40.03),(41.30±28.69)and(303.90±136.69)ng·h·mL^(-1),respectively,and the elimination half-life(t_(1/2))was(5.82±2.22),(1.08±0.01)and(4.95±2.53)h,respectively.Multiple dosing significantly in-creased the exposure of the three components.There were significant differences in exposure be-tween male and female rats,with higher exposure observed in female rats(P<0.05).The three active components were widely distributed in various tis-sues/organs,with the highest exposure observed in the gastrointestinal tract,followed by the liver and kidney.CONCLUSION:The UPLC-MS/MS method is accurate,sensitive,and reliable for the quantitative analysis of tetrahydropalmatine,nobiletin,and cos-tunolide.These three active components in Dali-tong extract can be absorbed,widely distributed in various tissues or organs,and rapidly metabolized/eliminated after oral administration.They are po-tential pharmacokinetic markers of Dalitong extract.

关 键 词：达立通浸膏 延胡索乙素 川陈皮素 木香烃内酯 药物代谢动力学 组织分布 

分 类 号：R965.2[医药卫生—药理学]