丁桂散脐部给药穴区局部药物代谢动力学研究

张永太; 侯晓琳; 沈慧芳; 田婷; 张恺; 黎哲; 冯年平

doi:10.3969/j.issn.1006-2157.2023.09.011

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丁桂散脐部给药穴区局部药物代谢动力学研究

实验研究 | 更新时间：2023-10-09

- 丁桂散脐部给药穴区局部药物代谢动力学研究
- Local pharmacokinetics of the transdermal drug delivery of Dinggui San in the umbilical region
- 北京中医药大学学报 2023年46卷第9期页码：1258-1266
- 作者机构：
  
  上海中医药大学　上海　201203
- 作者简介：
  
  张永太，男，博士，教授，博士生导师
  # 冯年平，博士，教授，博士生导师，主要研究方向：中药新型给药系统，E-mail：npfeng@shutcm.edu.cn
- 基金信息：
  
  国家自然科学基金面上项目(82074031);上海市东方学者特聘教授资助项目(TP2020054)
- DOI：10.3969/j.issn.1006-2157.2023.09.011
  中图分类号： R285
- 收稿日期：2023-04-13，
  
  网络出版日期：2023-07-11，
  
  纸质出版日期：2023-09-30
- 稿件说明：
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张永太, 侯晓琳, 沈慧芳, 等. 丁桂散脐部给药穴区局部药物代谢动力学研究[J]. 北京中医药大学学报, 2023,46(9):1258-1266.

ZHANG Yongtai, HOU Xiaolin, SHEN Huifang, et al. Local pharmacokinetics of the transdermal drug delivery of Dinggui San in the umbilical region[J]. Journal of beijing university of traditional chinese medicine, 2023, 46(9): 1258-1266.
张永太, 侯晓琳, 沈慧芳, 等. 丁桂散脐部给药穴区局部药物代谢动力学研究[J]. 北京中医药大学学报, 2023,46(9):1258-1266. DOI： 10.3969/j.issn.1006-2157.2023.09.011.

ZHANG Yongtai, HOU Xiaolin, SHEN Huifang, et al. Local pharmacokinetics of the transdermal drug delivery of Dinggui San in the umbilical region[J]. Journal of beijing university of traditional chinese medicine, 2023, 46(9): 1258-1266. DOI： 10.3969/j.issn.1006-2157.2023.09.011.

摘要

目的

采用微透析技术，比较丁桂散经脐部、脐部旁开与口服给药后，活性成分在皮肤组织中的局部药物代谢动力学(简称“药动学”)行为。

方法

SPF级雄性SD大鼠分为4组，即正常大鼠脐部给药组(N-CV8)、溃疡性结肠炎(UC)模型大鼠脐部给药组(UC-CV8)、UC模型大鼠神阙穴旁开给药组(UC-PA)、UC模型大鼠口服给药组(UC-oral)，每组4只。造模后第4天，分别在正常大鼠及模型大鼠的神阙与神阙旁开2 mm部位外敷(0.1 g/只)及灌胃丁桂散(0.1 g/只)。将微透析探针埋入各外敷组给药部位皮下组织、口服组神阙穴皮下组织。以20%乙醇生理盐水溶液作为灌流液，流速为0.2 mL/h进行灌流。给药15 min后，开始收集透析液，每30 min收集1次，共收集20次，持续600 min。透析液直接进高效液相色谱仪，检测其中主要有效成分丁香酚与桂皮醛的代谢物肉桂酸的含量。所得数据以DAS 2.1药动学分析软件进行非房室模型拟合，分析比较各组药动学参数。

结果

丁香酚与肉桂酸的微透析体外正向回收率分别为41.4%±2.6%和51.6%±2.1%，反向回收率分别为45.9%±1.5%和50.6%±0.6%；丁香酚与肉桂酸的体内平均回收率分别为40.4%和42.8%。各时间点下，各经皮给药组大鼠皮下组织中的丁香酚质量浓度均高于UC-oral(小于0.15 mg/L)，且UC-CV8最高。UC-CV8丁香酚局部血药浓度－时间曲线下面积(

AUC

0－t

)与峰浓度(

max

)均较N-CV8、UC-PA及UC-oral增加(

0.05)。大多数时间点下，UC-oral大鼠皮肤组织中肉桂酸质量浓度较低(小于0.15 mg/L)。在4个组中，UC-oral大鼠皮肤组织中肉桂酸

max

及

AUC

0－t

最低，UC-CV8最高，2组比较，差异有统计学意义(

0.05)。

结论

脐部给药提高了药物在局部皮肤组织中的吸收分布。皮肤微透析技术适合中药复方经皮给药评价。

Abstract

Objective

We sought to compare the local pharmacokinetics of the active ingredients in the skin after the transdermal administration of

Dinggui San

(powder made from cloves and cinnamon) on the CV8

the position beside the CV8

and oral administration using a microdialysis technique.

Methods

Male SD rats in a SPF grade were divided into four groups(

=4 each): the group of normal rats administered

Dinggui San

on CV8(N-CV8)

the group of ulcerative colitis rats administered on CV8(UC-CV8)

the group of ulcerative colitis rats administered on the position beside 2 mm CV8 group(UC-PA)

and the group of ulcerative colitis rats administered orally(UC-oral). After modeling

the rats in the group received the corresponding administration with 0.1 g each(external use or oral). A microdialysis linear probe was implanted into the subcutaneous tissues of the corresponding external administration regions or CV8 in UC-oral

and perfused with 20% ethanolic saline solution at a flow rate of 0.2 mL/h. After 15 min of administration

the receiving fluid was collected every 30 min

and altogether collected 20 times

lasted 600 min. The receiving fluid was collected and directly analyzed by HPLC for the determination of cinnamic acid

a metabolite of cinnamaldehyde

and eugenol

as the main active ingredients in

Dinggui San

. The data obtained were fitted to a non-compartment model using the DAS 2.1 pharmacokinetic analysis software to analyse and compare pharmacokinetic parameters.

Results

The forward recovery rates in vitro of eugenol and cinnamic acid were 41.4%±2.6% or 51.6%±2.1%

and the reverse recovery rates in vitro were 45.9%±1.5% or 50.6%±0.6%. The average recovery rates in vivo of eugenol and cinnamic acid were 40.4%

42.8%. At each time point

the mass concentration in the skin of eugenol of all external administration groups were higher than that of UC-oral(less than 0.15 mg/L)

and that of UC-CV8 was the highest. The area under the concentration-time curve from time 0 to last time of quantifiable concentration(

AUC

0-t

) and maximum concentration(

max

) of eugenol increased significantly

compared with N-CV8

UC-PA and UC-oral(

0.05). At the most time points

the mass concentration in the skin of cinnamic acid of UC-oral were lower(less than 0.15 mg/L). Of all the four groups

AUC

0-t

and

max

of cinnamic acid in UC-oral were the lowest and that in UC-CV8 highest. The differences of UC-oral to UC-CV8 were significant(

0.05).

Conclusion

The transdermal umbilical administration of

Dinggui San

improves the absorption and distribution of the active ingredients in the local skin tissues. The microdialysis technique seems to be suitable for evaluation of TCM compound prescription via percutaneous delivery.

关键词

Keywords

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