Pharmacokinetics of Sinapic Acid from Stir-fried Raphani Semen in Rats and Its PK-PD Correlation Analysis

Li LI; Xiao-jie YIN; Li LI; Lan WANG; Lei-lei GONG; Ri-xin LIANG

doi:10.13422/j.cnki.syfjx.20200446

您当前的位置：

首页 >

文章列表页 >

Pharmacokinetics of Sinapic Acid from Stir-fried Raphani Semen in Rats and Its PK-PD Correlation Analysis

Drug Metabolism | 更新时间：2021-02-09

- Pharmacokinetics of Sinapic Acid from Stir-fried Raphani Semen in Rats and Its PK-PD Correlation Analysis
- Chinese Journal of Experimental Traditional Medical Formulae Vol. 26, Issue 7, Pages: 109-116(2020)
- 作者机构：
  
  1.中国中医科学院　中药研究所，北京　 100700
  2.首都医科大学　北京妇产医院，北京　 100026
- 作者简介：
- 基金信息：
- DOI：10.13422/j.cnki.syfjx.20200446
  CLC： R2; R969.1; R28; C37; R943.1; O657
- Received：05 July 2019，
  
  Published Online：06 November 2019，
  
  Published：05 April 2020
- 稿件说明：
移动端阅览
Li LI, Xiao-jie YIN, Li LI, et al. Pharmacokinetics of Sinapic Acid from Stir-fried Raphani Semen in Rats and Its PK-PD Correlation Analysis[J]. Chinese journal of experimental traditional medical formulae, 2020, 26(7): 109-116.
DOI：

Li LI, Xiao-jie YIN, Li LI, et al. Pharmacokinetics of Sinapic Acid from Stir-fried Raphani Semen in Rats and Its PK-PD Correlation Analysis[J]. Chinese journal of experimental traditional medical formulae, 2020, 26(7): 109-116. DOI： 10.13422/j.cnki.syfjx.20200446.

摘要

目的：

研究炒莱菔子醇提物中芥子酸在正常大鼠体内的药代动力学特征以及在哮喘大鼠病理状态下的药代动力学-药效动力学(PK-PD)相关性。

方法：

正常大鼠分别单次灌胃低、中、高剂量(4.5，9，18 g·kg

-1

)的炒莱菔子醇提物，利用UHPLC-MS/MS测定不同时间点血浆中芥子酸含量，采用DAS 3.2.8软件进行数据分析以获取药代动力学参数；采用腹腔注射卵清蛋白佐以氢氧化铝建立大鼠哮喘模型，分别灌胃低、高剂量(4.5，9 g·kg

-1

)炒莱菔子醇提物，3周后眼底静脉丛取血，分离血浆和血清，UHPLC-MS/MS测定不同时间点血浆中芥子酸含量，利用酶联免疫吸附测定法(ELISA)测定血清中免疫球蛋白E(IgE)，白细胞介素-5(IL-5)，肿瘤坏死因子-

(TNF-

)活性，采用DAS 3.2.8软件进行PK-PD模型拟合以及数据分析。

结果：

正常大鼠灌胃给予低、中、高剂量炒莱菔子醇提物后，血浆中芥子酸药峰浓度(

max

)分别为(29.35±10.32)，(62.70±27.47)，(137.33±40.95) μg·L

-1;

药时曲线下面积(AUC

)分别为(92.83±27.16)，(240.74±75.09)，(633.95±195.88) μg·L

-1

·h；达峰时间(

max

)分别为(2.58±0.80)，(3.00±0)，(5.50±1.23) h；与炒莱菔子醇提物低剂量组比，炒莱菔子醇提物中、高剂量组的AUC

，平均滞留时间(MRT

)均显著增加(

0.05，

0.01)；芥子酸体内AUC

在4.5～18 g·kg

-1

线性依赖性良好。哮喘大鼠分别灌胃低、高剂量炒莱菔子醇提物后0.083，0.167 h，与模型组比较，血清中IL-5，IgE，TNF-

含量均有不同程度地降低(

0.05，

0.01)；血浆中芥子酸

max

分别为(58.43±27.94)，(61.16±18.79) μg·L

-1

；AUC

分别为(188.75±37.07)，(247.90±36.89) μg·L

-1

·h；AUC

，表观分布容积(

)和清除率(CL

)均随剂量增加而增加，最佳药动学模型拟合为血管外给药的一房室模型，PK-PD模型可能适用于间接连接模型。

结论：

哮喘大鼠体内芥子酸血药浓度与血清中IL-5，IgE，TNF-

含量存在一定的相关性，给药剂量和机能状态(病理或生理状态)均会影响炒莱菔子中芥子酸在大鼠体内的药代动力学行为，并与其平喘药效有一定的关联性。

Abstract

Objective:

To study the pharmacokinetics of sinapic acid from stir-fried Raphani Semen in normal rats and the correlation between pharmacokinetics-pharmacodynamics (PK-PD) in asthma rats.

Method:

Normal rats received 4.5

18 g·kg

-1

of stir-fried Raphani Semen by oral administration

respectively. Blood was taken from ophthalmic venous plexus at different time points according to the experimental design

the plasma concentration of sinapic acid was analyzed by UHPLC-MS/MS

and data analysis was performed using DAS 3.2.8 software to obtain the pharmacokinetic parameters. Rat asthma model was established by intraperitoneal injection of ovalbumin with aluminum hydroxide

and treated with ethanol extract of stir-fried Raphani Semen (low and high doses of 4.5

9 g·kg

-1

). After treatment for 3 weeks

taking blood at different time points

plasma and serum were separated. UHPLC-MS/MS was established for the determination of plasma concentration of sinapic acid

contents of interleukin-5 (IL-5)

immunoglobuin E (IgE)

tumor necrosis factor-

(TNF-

) in serum at different time points were detected by enzyme-linked immunosorbent assay (ELISA)

DAS 3.2.8 software was used for PK-PD model fitting and data analysis.

Result:

After normal rats were administrated with low

medium and high doses of stir-fried Raphani Semen

the peak concentration (

max

) of sinapic acid in plasma were (29.35±10.32)

(62.70±27.47)

(137.33±40.95) μg·L

-1

its area under the curve (AUC

) were (92.83±27.16)

(240.74±75.09)

(633.95±195.88) μg·L

-1

·h

its peak time (

max

) were (2.58±0.80)

(3.00±0)

(5.50±1.23) h

respectively. Compared with the low dose group

AUC

and mean retention time (MRT

) were all increased in the medium and high dose groups

showing statistical differences (

0.05

0.01). The linear relationship of AUC

in sinapic acid was good within the dose range of 4.5-18 g·kg

-1

. After treating with ethanol extract of stir-fried Raphani Semen for 0.083

0.167 h

compared with the model group of asthmatic rats

serum levels of IL-5

IgE

TNF-

of the medication groups were decreased to different degrees (

0.05

0.01).

max

of sinapic acid in the low and high dose groups were (58.43±29.94)

(61.16±18.79) μg·L

-1

its AUC

were (188.75±37.07)

(247.90±36.89) μg·L

-1

·h

respectively. AUC

apparent volume of distribution (

) and clearance rate (CL

) all increased significantly with the increase of dose. The best pharmacokinetic model of sinapic acid was fitted as a one-compartment model for extravascular administration

PK-PD model may be applicable to indirect connection model.

Conclusion:

The plasma concentration of sinapic acid is correlated with contents of IL-5

IgE and TNF-

dosage and functional state (pathological or physiological state) can affect the pharmacokinetic behavior of sinapic acid from stir-fried Raphani Semen in rats

and it has a certain correlation with the anti-asthmatic effect.

关键词

Keywords

references

王番，宋颖，白娟，等．药代动力学-药效学模型的应用进展 [J]．中国临床药理学杂志， 2018 ， 34 ( 22 ): 2667 - 2670 .

张茜，周洪雷，朱立俏，等．莱菔子化学成分研究进展 [J]．辽宁中医药大学学报， 2018 ， 20 ( 4 ): 137 - 140 .

苏慧，岳琳，刘颖，等．芥子及莱菔子饮片炮制前后物质基础变化规律分析 [J]．中国实验方剂学杂志， 2018 ， 24 ( 7 ): 23 - 26 .

朱立俏，张元元，于绍华，等．莱菔子炮制前后HPLC指纹图谱及主要成分含量变化研究 [J]．中药新药与临床药理， 2018 ， 29 ( 5 ): 614 - 621 .

M RAISH , A AHMAD , A M AHMAD ， et al . Sinapic acid ameliorates bleomycin-induced lung fibrosis in rats [J]． Biomed Pharmacother ， 2018 ， 108 ( 1 ): 224 - 231 .

杨瑛洁，李淑燕，胡国伟，等．硫代葡萄糖苷的降解途径及其产物的研究进展 [J]．西北植物学报， 2011 ， 31 ( 7 ): 1490 - 1496 .

马丛丛，许继取，韩领，等．芥子酸及其生物活性研究进展 [J]．中国油脂， 2016 ， 41 ( 5 ): 75 - 79 .

T SOTELO , M LEMA , P SOENGAS ， et al . In vitro activity of glucosinolates and their degradation products against brassica-pathogenic bacteria and fungi [J]． Appl Environ Microb ， 2015 ， 81 ( 1 ): 432 - 440 .

K GROSSER , N M VAN DAM ． A straightforward method for glucosinolate extraction and analysis with high-pressure liquid chromatography (HPLC) [J]． J Vis Exp ， 2017 ， doi: 10.3791/55425 http://dx.doi.org/10.3791/55425 .

王群，孙忠迪，刘梅，等．炒莱菔子中芥子碱对高血脂大鼠血脂水平的影响 [J]．医学研究杂志， 2013 ， 42 ( 5 ): 60 - 62 .

刘晓舒，裴晓琳，王继鹏，等．咳必停镇咳祛痰平喘作用 [J]．中国公共卫生， 2018 ， 34 ( 6 ): 830 - 833 .

裴星，韩勇，张占华，等．芥子酸对高糖诱导下大鼠血管平滑肌细胞增殖和凋亡的影响 [J]．中国病理生理杂志， 2016 ， 32 ( 7 ): 1174 - 1179 .

周艳丽，阮研硕，劳文艳，等．哮喘动物模型的建立方法研究进展 [J]．环境与健康杂志， 2017 ， 34 ( 10 ): 931 - 936 .

Y HE , X H LOU , Z JIN ， et al . Mahuang decoction mitigates airway inflammation and regulates IL-21/STAT3 signaling pathway in rat asthma model [J]． J Ethnopharmacol ， 2018 ， 224 : 373 - 380 .

S H KIM , Y C LEE ． Piperine inhibits eosinophil infiltration and airway hyper responsiveness by suppressing T cell activity and Th2 cytokine production in the ovalbumin-induced asthma model [J]． J Pharm Pharmacol ， 2009 ， 61 ( 3 ): 353 - 359 .

劳文艳，阮研硕，周艳丽，等．两种大鼠哮喘模型建立方法的比较 [J]．北京联合大学学报：自然科学版， 2017 ， 31 ( 3 ): 54 - 58 .

陈锡培，苏妙珠，蔡宇文．止咳定喘汤对咳嗽变异性哮喘模型大鼠肺表面活性蛋白表达的影响 [J]．中医药导报， 2018 ， 24 ( 13 ): 23 - 27 .

乡世健，盛华芳，吕亚梅，等．冬病夏治方穴位贴敷对哮喘豚鼠气道炎症及肠道菌群的影响 [J]．中国实验方剂学杂志， 2018 ， 24 ( 9 ): 95 - 102 .

李海霞，张勇华，任晓丹，等．建立RSV联合OVA诱发幼年大鼠哮喘模型的方法 [J]．湖南中医药大学学报， 2018 ， 38 ( 12 ): 1371 - 1373 .

L L GONG , H Y XU , L WANG ， et al . Identification and evaluation of the chemical similarity of Yindan xinnaotong samples by ultra high performance liquid chromatography with quadrupole time-of-flight mass spectrometry fingerprinting [J]． J Sep Sci ， 2016 ， 39 ( 3 ): 611 - 622 .

李涛，王怡薇，王彦礼，等．黄芩汤在大鼠发热状态下药效学及药代动力学特征研究 [J]．药学学报， 2014 ， 49 ( 10 ): 1418 - 1425 .

陈立．小承气汤类方物质基础、药效学和药代动力学比较研究 [D]．北京：中国中医科学院， 2015 .

高小明，杨瑞，夏素霞，等．生脉注射液中人参皂苷Rc在心绞痛患者体内的PK-PD相关性 [J]．药物评价研究， 2018 ， 41 ( 7 ): 1241-1245，1259 .

巩仔鹏，胡建春，李梅，等．基于大鼠脑缺血再灌注损伤模型建立辛芍组方中灯盏乙素和芍药苷的PK-PD结合模型 [J]．中国实验方剂学杂志， 2018 ， 24 ( 1 ): 74 - 78 .

詹淑玉，邵青，李正，等．生脉注射液中人参皂苷Rg 1 ，Rb 1 在心肌缺血大鼠体内的药动学-药效学结合研究 [J]．中国中药杂志， 2014 ， 39 ( 7 ): 1300 - 1305 .

王丽，胡樱凡，童东，等．黄连碱对内毒素发热大鼠解热作用的PK-PD研究 [J]．中国药理学通报， 2017 ， 33 ( 4 ): 552 - 556 .

龚小红，周忆梦，郑立，等．大黄治疗阳虚便秘模型大鼠的整合PK/PD研究 [J]．药学学报， 2018 ， 53 ( 4 ): 561 - 566 .

陈璟，吕志阳，汪洁，等．银杏总内酯在脑缺血损伤模型大鼠体内的PK-PD研究 [J]．中草药， 2018 ， 49 ( 4 ): 885 - 890 .

杨永茂．大黄蒽醌保护肠粘膜屏障损伤的PK-PD结合模型研究 [D]．成都：成都中医药大学， 2011 .

严龙．中药仙茅在大鼠体内的PK-PD模型初探 [D]．曲阜：曲阜师范大学， 2014 .

黄晖，朱慧志，刘璐，等．阳和平喘颗粒不同阶段干预对哮喘大鼠气道黏液高分泌及血清IL-13水平影响 [J]．辽宁中医药大学学报， 2019 ， 21 ( 2 ): 16-19，225 .

张洁，朱慧志，刘向囯，等．阳和平喘颗粒对哮喘模型大鼠血清IL-4、IL-5和IL-13的影响 [J]．辽宁中医杂志， 2018 ， 45 ( 11 ): 2426-2428，2463 .

姚欢，刘璐，朱慧志，等．阳和平喘颗粒早期和晚期干预对哮喘大鼠支气管肺泡灌洗液中白细胞介素-5和白细胞介素-9的影响 [J]．安徽中医药大学学报， 2017 ， 36 ( 4 ): 63 - 66 .

P ARORA , S H ANSARI , V ANJUM ， et al . Investigation of anti-asthmatic potential of Kanakasava in ovalbumin-induced bronchial asthma and airway inflammation in rats [J]． J Ethnopharmacol ， 2017 ， 197 : 242 - 249 .

翟慧媛，陈磊垚，王东旭，等．钩薄过敏颗粒对咳嗽变异性哮喘大鼠肺泡灌洗液IL-4、IL-5、IFN- γ 水平影响 [J]．世界中西医结合杂志， 2016 ， 11 ( 12 ): 1668 - 1671 .

K KOUADIO , K C ZHENG , A A TOURE ， et al . IL-4 and IL-5 secretions predominate in the airways of Wistar rats exposed to toluene diisocyanate vapor [J]． J Prev Med Public Health ， 2014 ， 47 ( 1 ): 57 - 63 .

徐增梅，丁伟伟，尹婷婷，等．麻芍平喘汤对支气管哮喘大鼠气道重塑及IL-5、IL-13影响研究 [J]．实用中医药杂志， 2014 ， 30 ( 12 ): 1074 - 1075 .

吴文娟，董晓斐，李娇艳，等．咳喘宁雾化吸入对哮喘大鼠肺泡灌洗液白介素-5与嗜酸性粒细胞的影响 [J]．湖南中医药大学学报， 2014 ， 34 ( 1 ): 19-21，33 .

Views

下载量

CSCD

Alert me when the article has been cited

提交

Tools

Publicity Resources

Clinical Comprehensive Evaluation of Zhichuanling Oral Liquid in Treatment of Asthma and Considerations for Cultivating High-value Patents

Attenuation of Airway Inflammation and Airway Remodeling in Ovalbumin Asthmatic Rats by Artemisinin through PI3K/Akt Signaling Pathway

Modified Wuhutang Alleviates Airway Inflammation and Down-regulates Expression of Muc5AC， STAT3， NF-κB， and NLRP3 in Lung Tissues of RSV-infected Asthmatic Mice

Mashao Pingchuan Decoction Inhibites Autophagy in Airway Epithelial Cells Through PI3K/Akt/mTOR Signaling Pathway

Effect of Yifei Huatan Decoction on Relieving Airway Hyperviscosity in Asthmatic Rats with Spleen Deficiency Syndrome and Its Mechanism

Related Author

YANG Shuo

LI Haiyan

XIE Yanming

WANG Lianxin

CHENGFENG Jingming

CUI Xin

LI Lixun

WANG Yanmei

Related Institution

Institute of Information on Traditional Chinese Medicine，China Academy of Chinese Medical Sciences

Institute of Basic Research in Clinical Medicine，China Academy of Chinese Medical Sciences

Henan Provincial Hospital of Traditional Chinese Medicine（TCM）/Second Affiliated Hospital of Henan University of TCM

Putuo Hospital， Shanghai University of TCM

Children's Hospital of Shanghai， Children's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine

AI问答

Postal code：100700
Tel：010-84076882 Email：syfjx_2010@188.com
Technical support is provided by Beijing Founder electronics co., LTD 京ICP备11006657号-10 京公网安备11010802024621
It is recommended to read the content of this site in Chrome&IE9+. Please switch to extreme mode in browser 360.
Cookies We use cookies to help provide and enhance our service and tailor content. By continuing, you agree to the use of cookies.

⁰