Published online Jun 14, 2020. doi: 10.3748/wjg.v26.i22.3056
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
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.
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.
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.
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.
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.
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.
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.