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 Cmax, Ka, t1/2, AUC(0−t) and AUC(0−∞) of troxipide were significantly increased in rats with GU compared with NC rats. The Vz, K10 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.
Highlights
Troxipide is widely used to treat gastric ulcer (GU) in the clinic
The results suggested that the ulcer area and ulcer index were markedly increased (P < 0.01) in the gastric ulcer group (GUG) compared to the normal control group (NCG), high-dose troxipide group (THG), medium-dose troxipide group (TMG) and low-dose troxipide group (TLG)
The pharmacokinetic parameters observed for troxipide were significantly different in GU rats when compared with normal control (NC) rats
Summary
A lack of systematic metabolic, pharmacokinetic and pharmacological studies limits its clinical use. 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. Detailed studies on the metabolites, pharmacokinetics and therapeutic mechanisms of troxipide in rats with GU are lacking, limiting the clinical use of this drug. Drug metabolism plays an important role in optimizing pharmacokinetics, pharmacodynamics, and safety properties, which could help researchers understand the major soft spots to the potential metabolism liability of a drug and optimize lead compounds for further development. In vitro and in vivo metabolic, pharmacokinetic and pharmacodynamic studies are essential parts of the drug discovery and development p rocesses[33]
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