Basic Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jun 14, 2020; 26(22): 3056-3075
Published online Jun 14, 2020. doi: 10.3748/wjg.v26.i22.3056
Optimal dosing time of Dachengqi decoction for protection of extrapancreatic organs in rats with experimental acute pancreatitis
Jia-Qi Yao, Lin Zhu, Yi-Fan Miao, Lv Zhu, Huan Chen, Ling Yuan, Jing Hu, Xiao-Lin Yi, Qiu-Ting Wu, Xi-Jing Yang, Mei-Hua Wan, Wen-Fu Tang
Jia-Qi Yao, Yi-Fan Miao, Lv Zhu, Huan Chen, Ling Yuan, Jing Hu, Xiao-Lin Yi, Qiu-Ting Wu, Mei-Hua Wan, Wen-Fu Tang, Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
Lin Zhu, Digestive System Department, Sichuan Integrative Medicine Hospital, Chengdu 610041, Sichuan Province, China
Xi-Jing Yang, Animal Experiment Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
Author contributions: Tang WF designed the research; Yao JQ, Zhu L, Miao YF, Chen H, Yuan L, Hu J, Yi XL, and Wu QT performed the research; Yao JQ, Zhu L, and Miao YF analyzed the data; Yang XJ were responsible for the drafting of the paper; Wan MH contributed new reagents or analytic tools; Tang WF and Wan MH obtained funding and provided study supervision.
Supported by the National Natural Science Foundation of China, No. 81603480 and No. 81573857.
Institutional animal care and use committee statement: This study was reviewed and approved by the Institutional Animal Care and Use Committee of West China Hospital of Sichuan University. All experiments were reviewed and approved by the Institution Animal Care and Use Committee of Sichuan University (Chengdu, China; protocol number: 2019003A).
Conflict-of-interest statement: None of the authors have any conflicts of interest to declare.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Wen-Fu Tang, PhD, Professor, Department of Integrative Medicine, West China Hospital, Sichuan University, No. 37, Guoxue Lane, Wuhou District, Chengdu 610041, Sichuan Province, China.
Received: January 21, 2020
Peer-review started: January 21, 2020
First decision: February 27, 2020
Revised: March 26, 2020
Accepted: May 13, 2020
Article in press: May 13, 2020
Published online: June 14, 2020
Research background

Acute pancreatitis (AP) is an inflammatory pancreatic disorder associated with substantial morbidity and mortality, and the severe form of AP is commonly complicated by multiple extrapancreatic organ dysfunction. Dachengqi decoction (DCQD) is an effective prescription for the treatment of AP, however, current AP guidelines do not provide specific guidance on the optimal time to take this Chinese herbal medicine orally. Our previous study proved that administering DCQD too early may aggravate the pathological damage to the pancreas, while the effect of administration time on multiple extrapancreatic organs in AP rats is still unclear. Therefore, investigations of the optimal administration time of DCQD for the protection of multiple extrapancreatic organs are urgently required.

Research motivation

DCQD has been shown to protect multiple organs from injury caused by an excessive inflammatory response in AP, and we confirmed that the anti-inflammatory effect was associated with its tissue distribution. This study aimed to screen the appropriate oral administration time of DCQD for the protection of extrapancreatic organs in AP rats based on the pharmacokinetic and pharmacodynamic evidence, and to provide an experimental basis for future clinical application of DCQD.

Research objectives

To identify the optimal administration time of DCQD for the protection of extrapancreatic organs in experimental AP rats and observe the anti-inflammatory efficacy at different times after administration.

Research methods

The current experiment was divided into pharmacokinetic and pharmacodynamic parts. The AP model was established with 3.5% sodium taurocholate. In the pharmacokinetic study, the concentrations of the DCQD components in serum and organ tissues were measured by HPLC-MS/MS, which is a sensitive, accurate, and reproducible method, and the pharmacokinetic parameters (C max, T max, T 1/2, and AUC 0 → t) were calculated with DAS 2.0.1. In the pharmacodynamic study, the levels of serum inflammatory cytokines (IL-6 and IL-10) were measured by enzyme-linked immunosorbent assay, and amylase levels were measured via a HITACHI automatic biochemical analyzer. All histopathological sections were observed and scored by two independent blinded pathologists using different scoring systems specific to different tissues. Additionally, Graph Pad Prism 7.0 software was used for the data analyses of both parts of the study.

Research results

In the pharmacokinetic study, the T max and C max values of most components were lower in the AP model groups, and the major components of DCQD had lower AUC and C max values in these groups. The later (12 h and 24 h) time points of oral dosing with DCQD resulted in higher C max values, larger AUC 0 → t values, and longer t1/2 values for these monomers, accompanied by higher concentrations of most components in the target extrapancreatic organ tissues. In the pharmacodynamic study, delayed administration of DCQD resulted in lower IL-6 and amylase levels and higher IL-10 levels, and pathological injury of multiple extrapancreatic organ (liver, lung, kidney, and intestine) tissues was slightly less at 4 h after administration, while the results were similar between the treatment and corresponding control groups at 24 h after administration.

This study provides some information on the effect of administration time on extrapancreatic organs in AP rats, but elucidation of the specific mechanism needs further study. Relevant pharmacokinetics and pharmacodynamics analysis should be considered to provide more systematic and comprehensive evidence for the clinical application of this Chinese herbal formula.

Research conclusions

This study suggests that early administration of DCQD may inhibit the pharmacokinetic process of the major DCQD components in serum and multiple extrapancreatic organ tissues, and delayed administration time may be more helpful for alleviating the inflammatory reaction and pathological injury in multiple extrapancreatic organs. Importantly, multiple-dose administration of DCQD is well worth considering for the steady-state effect in future animal experiments or clinical applications.

Research perspectives

Although we have found some of the potential components of DCQD in alleviating AP, and the therapeutic effect of DCQD on AP has been confirmed in a large number of in vivo and in vitro experiments, the underlying molecular mechanisms are not well established. Further investigation combing the identification of more active components, potential targets, and/or signal pathway analysis is urgently required to make a deeper and more comprehensive understanding of the therapeutic mechanism of DCQD in the treatment of AP.