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中国临床药理学与治疗学 ›› 2024, Vol. 29 ›› Issue (1): 37-51.doi: 10.12092/j.issn.1009-2501.2024.01.004

• 基础研究 • 上一篇    下一篇

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

张渊茂1,张  冉1,廖睿伟1,陶  琳2,孟秀秀1,徐 晨1,高芳芳1,阿基业1,王广基1   

  1. 1中国药科大学药物代谢动力学重点实验室,南京  210009,江苏;2南昌弘益药业有限公司,南昌  330006,江西

  • 收稿日期:2023-05-11 修回日期:2023-07-03 出版日期:2024-01-26 发布日期:2024-01-15
  • 通讯作者: 阿基业,男,研究员,博士生导师,研究方向:药物代谢动力学、代谢组学与药代动力学结合研究、代谢与药物毒性/药效作用机制研究等。 E-mail:jiyea@cpu.edu.cn
  • 作者简介:张渊茂,男,硕士在读,研究方向:中药代谢组学、药物代谢动力学。 E-mail:zhangym802@163.com

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

ZHANG Yuanmao1, ZHANG Ran1, LIAO Ruiwei1, TAO Lin2, MENG Xiuxiu1, XU Chen1, GAO Fangfang1, A Jiye1, WANG Guangji1   

  1. 1Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, Jiangsu, China; 2Nanchang Hongyi Pharmaceutical Co.,Ltd, Nanchang 330006, Jiangxi, China 
  • Received:2023-05-11 Revised:2023-07-03 Online:2024-01-26 Published:2024-01-15

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(Cmax)分别为(13.73±7.50)、(27.01±17.69)、(66.73±29.94) ng/mL,曲线下面积(AUC0-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(t1/2)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(Cmax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。

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

Abstract:

AIM: To investigate the pharmacokinetic 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 characteristics and tissue distribution. RESULTS: After a single oral administration, the three active components were rapidly absorbed into the body, with a peak concentration (Cmax) of (13.73±7.50), (27.01±17.69) and (6.73±29.94) ng/mL for tetrahydropalmatine, nobiletin, and costunolide, respectively. The time to reach the peak concentration (Tmax) was (1.40 ± 0.93), (0.63 ± 0.28) and (2.38 ± 8.81) h, respectively. 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 increased the exposure of the three components. There were significant differences in exposure between male and female rats, with higher exposure observed in female rats (P<0.05). The three active components were widely distributed in various tissues/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 costunolide. These three active components in Dalitong extract can be absorbed, widely distributed in various tissues or organs, and rapidly metabolized/eliminated after oral administration. They are potential pharmacokinetic markers of Dalitong extract.

Key words: Dalitong extract, tetrahydropalmatine, nobiletin, costunolide, pharmacokinetics, tissue distribution

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