采用液相色谱-质谱联用技术对大豆异黄酮衍生物3-(4-氯苯基)-7-[2-(哌嗪-1-基)乙氧基]-4H-苯并吡喃-4-酮在正常大鼠体内的药代动力学研究

doi:10.5246/jcps.2025.07.047

中国药学(英文版) ›› 2025, Vol. 34 ›› Issue (7): 633-643.DOI: 10.5246/jcps.2025.07.047

采用液相色谱-质谱联用技术对大豆异黄酮衍生物3-(4-氯苯基)-7-[2-(哌嗪-1-基)乙氧基]-4H-苯并吡喃-4-酮在正常大鼠体内的药代动力学研究

郝军荣¹^,², 连孟强³, 李双⁴^,⁵, 殷宏艳¹^,², 郭春燕¹^,²^,^*()

^1. 河北北方学院药学院, 河北张家口 075000
^2. 河北省神经药理学重点实验室, 河北张家口 075000
^3. 优吉(天津)医药科技有限公司, 天津 300450
^4. 健垣精准医药(张家口)有限公司, 河北张家口 075000
^5. 河北师范大学生命科学学院河北省抗肿瘤分子靶标技术创新中心, 河北石家庄 050024

收稿日期:2025-03-27 修回日期:2025-04-16 接受日期:2025-04-23 出版日期:2025-07-31 发布日期:2025-07-31
通讯作者: 郭春燕

Pharmacokinetic study of 3-(4-chlorophenyl)-7-[2-(piperazin-1-yl)ethoxy]-4H-chromen-4-one, a derivative of soybean isoflavone by LC-MS/MS in normal rats

Junrong Hao¹^,², Mengqiang Lian³, Shuang Li⁴^,⁵, Hongyan Yin¹^,², Chunyan Guo¹^,²^,^*()

¹ Department of Pharmacy, Hebei North University, Zhangjiakou 075000, Hebei, China
² Hebei Key Laboratory of Neuropharmacology, Zhangjiakou 075000, Hebei, China
³ Youji (Tianjin) Medicine Technology Co., Ltd., Tianjin 300450, China
⁴ Jianyuan Precision Medicines (Zhangjiakou) Co., Ltd., Zhangjiakou 075000, Hebei, China
⁵ Hebei Anti-Tumor Molecular Target Technology Innovation Center, College of Life Science, Hebei Normal University, Shijiazhuang 050024, Hebei, China

Received:2025-03-27 Revised:2025-04-16 Accepted:2025-04-23 Online:2025-07-31 Published:2025-07-31
Contact: Chunyan Guo
Supported by:
Scientific Research Projects of Hebei North University (Grant No. XJ2024022).

摘要/Abstract

摘要：

3-(4-氯苯基)-7-[2-(哌嗪-1-基)乙氧基]-4H-苯并吡喃-4-酮(CPEO-43)是大豆异黄酮(Soybean isoflavone, SI)的一种衍生物, 通过在天然大豆异黄酮的结构中引入氯元素和哌嗪基团而合成的。体外实验已证实, CPEO-43对A549细胞和 HCT116细胞也具有明显的抑制作用。为了进一步开发和利用CPEO-43, 本研究旨在建立并验证液相色谱-质谱联用(LC-MS/MS)定量分析方法, 用于CPEO-43 的药代动力学研究。正常大鼠灌胃不同剂量(2、6和20 mg/kg)的CPEO-43后, 于不同时间点眼底静脉丛取血, 利用LC-MS/MS技术测定不同时间点CPEO-43的血药浓度, 并采用药代动力学软件DAS2.0计算该化合物的药代动力学参数。结果表明所建立的LC-MS/MS方法符合中国药典(CHP)有关生物分析方法验证的标准, 可用于CPEO-43的药代动力学研究。运用药代动力学软件DAS 2.0非房室模型成功计算了该化合物的不同剂量的C_max, T_max, t_1/2, AUC_0–∞, MRTs, CL, Vd等药代动力学参数。依次分别为62.0 ± 10.5, 222.0 ± 28.7和1384.5 ± 376.4 ng/mL, 8.5 ± 1.2, 6.0 ± 0.0和11.0 ± 6.2 h, 15.6, 15.0和18.5 h, 1517.8 ± 317.0, 5328.7 ± 864.4和45556.3 ± 22735.6 ng·h/mL, 17.8 ± 1.2, 17.7 ± 0.8和20.0 ± 3.2 h, 1370.3 ± 305.9, 1153.5 ± 205.6和505.3 ± 179.8 mL/kg/h, 30843.0 ± 7458.0, 24344.0 ± 5237.0和13950.3 ± 5996.9 mL/kg。这些特性对于理解药物的体内过程、制定给药方案以及评估药物的安全性和有效性具有重要意义。

关键词: 3-(4-氯苯基)-7-[2-(哌嗪-1-基)乙氧基]-4H-苯并吡喃-4-酮, 大豆异黄酮, 液相色谱-质谱联用技术, 药物代动力学

Abstract:

3-(4-Chlorophenyl)-7-[2-(piperazin-1-yl)ethoxy]-4H-chromen-4-one (CPEO-43) is a derivative of soybean isoflavone (SI), synthesized by introducing a chlorine atom and a piperazine group into the structure of natural SI. In vitro experiments have demonstrated that CPEO-43 exhibits a notable inhibitory effect on both A549 cells and HCT116 cells. For the further development and utilization of CPEO-43, this study aims to establish and validate a liquid chromatography-tandem mass spectrometry (LC-MS/MS) quantitative analysis method for the pharmacokinetic study of CPEO-43. Normal rats were intragastrically administered different doses (2, 6, and 20 mg/kg) of CPEO-43, and blood was taken from the ocular venous plexus at different time points. The blood concentration of CPEO-43 at different time points was determined using LC-MS/MS technology, and the pharmacokinetic parameters of the compound were calculated using the pharmacokinetic software DAS. The results indicated that the established LC-MS/MS method complies with the standards for bioanalytical method validation in the Chinese Pharmacopoeia (CHP) and can be applied to the pharmacokinetic study of CPEO-43. The pharmacokinetic software DAS non-compartmental model was successfully used to calculate the C_max, T_max, t_1/2, AUC_0–∞, MRTs, CL, and Vd pharmacokinetic parameters of the compound at different doses. The results were as follows: 62.0 ± 10.5, 222.0 ± 28.7, and 1384.5 ± 376.4 ng/mL; 8.5 ± 1.2, 6.0 ± 0.0, and 11.0 ± 6.2 h; 15.6, 15.0, and 18.5 h; 1517.8 ± 317.0, 5328.7 ± 864.4, and 45556.3 ± 22735.6 ng·h/mL; 17.8 ± 1.2, 17.7 ± 0.8, and 20.0 ± 3.2 h; 1370.3 ± 305.9, 1153.5 ± 205.6, and 505.3 ± 179.8 mL/kg/h; 30843.0 ± 7458.0, 24344.0 ± 5237.0, and 13950.3 ± 5996.9 mL/kg. These characteristics are of great significance for understanding the in vivo process of the drug, formulating dosing regimens, and evaluating the safety and efficacy of the drug.

Key words: 3-(4-Chlorophenyl)-7-[2-(piperazin-l-yl)ethoxy]-4H-chromen-4-one, Soybean isoflavone, LC-MS/MS, Pharmacokinetics

Supporting:

郝军荣, 连孟强, 李双, 殷宏艳, 郭春燕. 采用液相色谱-质谱联用技术对大豆异黄酮衍生物3-(4-氯苯基)-7-[2-(哌嗪-1-基)乙氧基]-4H-苯并吡喃-4-酮在正常大鼠体内的药代动力学研究[J]. 中国药学(英文版), 2025, 34(7): 633-643.

Junrong Hao, Mengqiang Lian, Shuang Li, Hongyan Yin, Chunyan Guo. Pharmacokinetic study of 3-(4-chlorophenyl)-7-[2-(piperazin-1-yl)ethoxy]-4H-chromen-4-one, a derivative of soybean isoflavone by LC-MS/MS in normal rats[J]. Journal of Chinese Pharmaceutical Sciences, 2025, 34(7): 633-643.

图/表 4

Figure 1. Typical chromatograms obtained from blank plasma (A, m/z 271→153.0; B, m/z 385→113.1) and plasma samples containing genistein (C, m/z 271→153.0) and CPEO-43 (D, m/z 385→113.1).

Figure 2. Calibration curve of CPEO-43 standard solutions.

Figure 3. Mean concentration-time profiles of CPEO-43 at different doses after intragastric administration to mice (A. 2 mg/kg, n = 6; B. 6 mg/kg, n = 6; C. 20 mg/kg, n = 4).

Table 1. Pharmacokinetic parameters (2 mg/kg, n = 6; 6 mg/kg, n = 6; 20 mg/kg, n = 4).

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采用液相色谱-质谱联用技术对大豆异黄酮衍生物3-(4-氯苯基)-7-[2-(哌嗪-1-基)乙氧基]-4H-苯并吡喃-4-酮在正常大鼠体内的药代动力学研究

Pharmacokinetic study of 3-(4-chlorophenyl)-7-[2-(piperazin-1-yl)ethoxy]-4H-chromen-4-one, a derivative of soybean isoflavone by LC-MS/MS in normal rats

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