Metabolites profiling and pharmacokinetics of troxipide and its pharmacodynamics in rats with gastric ulcer

Abstract

Troxipide is widely used to treat gastric ulcer (GU) in the clinic. However, a lack of systematic metabolic, pharmacokinetic and pharmacological studies limits its clinical use. This study aimed to firstly explore the metabolic, pharmacokinetic and pharmacological mechanisms of troxipide in rats with GU compared to normal control (NC) rats. First, metabolic study was perormed by a highly selective, high-resolution mass spectrometry method. A total of 45 metabolites, including 9 phase I metabolites and 36 phase II metabolites, were identified based on MS/MS spectra. Subsequently, the pharmacokinetics results suggested that the C max , K a , t 1/2 , AUC (0−t) and AUC (0−∞) of troxipide were significantly increased in rats with GU compared with NC rats. The V z , K 10 and absolute bioavailability of troxipide were obviously decreased in rats with GU compared with NC rats, and its tissue distribution (in the liver, lung and kidney) was significantly different between the two groups of rats. Additionally, the pharmacodynamic results suggested that the levels of biochemical factors (IL-17, IL-6, TNF-α, IFN-γ, AP-1, MTL, GAS, and PG-II) were significantly increased, the PG-Ӏ level was obviously decreased, and the protein expression levels of HSP-90, C-Cas-3 and C-PARP-1 were markedly increased in rats with GU compared with NC rats. The above results suggested that the therapeutic mechanisms underlying the metabolic, pharmacokinetic and pharmacological properties of troxipide in vivo in rats deserve further attention based on the importance of troxipide in the treatment of GU in this study, and these mechanisms could be targets for future studies. Gastric ulcer, (GU) a common disease in the clinic, is a peptic ulcer that affects humans of all ages. It is associated with morbidity and mortality, and has become a medical-social problem of global importance that has received increased attention 1-4. The frequent occurrence of GU between the cardia and pylorus mainly results form tissue damage caused by digestive juices decomposing the gastric mucosa, especially near the lesser curvature of the stomach and gastric antrum 5-8. Currently, GU is a widely considered multifactorial disease because it is related to gastric acid, gastric pepsin, infection, physical fitness, environment, living habits and so on 9-11. If not treated adequately, GU can lead to serious complications such as perforation and bleeding 12-15. In addition, the acetic acid-induced GU in rats is most similar to GU in humans 16-20. Here, acetic acid-induced GU is more severe than other GU models (ethanol-, ligation-and reserpine-induced models), and is the most commonly used model for experimental research on GU 21,22. Moreover,this model is reproducible and reliable. Therefore, we selected a rat model of GU to evaluate relative studies of troxipide in the paper. Troxipide (3,4,5-trimethoxy-N-3-piperidinyl, Fig. 1), a defensive factor-enhancing therapeutic agent for gastritis and GU that exerts inhibitory, therapeutic and preventive effects to specifically tho...

Advances in high‐resolution mass spectrometry applied to pharmaceuticals in 2020: A whole new age of information

“…identified the 45 phase I and II metabolites of troxipide by using UHPLC‐Q‐TOF‐MS through accurate mass measurements and MS/MS fragmentation interpretation by analyzing plasma, fecal, and urine samples to understand the metabolic pathways of the drug. This is the first time these 45 metabolites have been reported for troxipide thereby filling an information gap 62 …”

“…61 Troxipide is a therapeutic agent for gastritis and gastric ulcer. 62 Detailed studies concerning metabolites, pharmacokinetics, and mechanism are missing thereby limiting the clinical use of the drug. Guo et al identified the 45 phase I and II metabolites of troxipide by using UHPLC-Q-TOF-MS through accurate mass measurements and MS/MS fragmentation interpretation by analyzing plasma, fecal, and urine samples to understand the metabolic pathways of the drug.…”

“…This is the first time these 45 metabolites have been reported for troxipide thereby filling an information gap. 62 Melanotan II is a cyclic heptapeptide drug that has been shown to increase insulin sensitivity, increase skin pigmentation, and treat sexual dysfunction in various preclinical and clinical studies. 63 together with network protein analysis to identify and quantify the proteome's changes.…”

Overexpression of HSP27 accelerates stress‐induced gastric ulcer healing via the CXCL12/CXCR4 axis

“…6 Heat shock proteins (HSPs) are emerging as crucial regulators of gastric inflammation and ulcer healing. 9 However, unlike other HSPs such as HSP70 25 and HSP90, 26 the specific role of HSP27 in gastric ulcer remains unclear. Herein, we found that HSP27 contributes to ulcer healing by promoting cell proliferation, migration and angiogenesis, suggesting its potential involvement in stressinduced gastric ulcer through modulation of the CXCL12/CXCR4 axis.…”

A pattern-recognition-based clustering method for non-invasive diagnosis and classification of various gastric conditions

“…Helicobacter pylori (H. pylori) infection is considered to be the most important risk factor for the development of PUD and the prevalence of the infection is as high as 90% in developing countries. [4][5][6] Patients with PUD may remain asymptomatic or symptomatic, and because of undefined risk factors along with a lack of specific symptoms at the early stages, the diagnosis is often delayed, leading to poor prognosis and high rates of recurrence of the disease. [7][8][9] However, the conventional endoscopic with biopsy-based invasive methods are not only suitable for early diagnosis, but also inappropriate for widespread population-screening including infants, children, pregnant women, and seniors.…”