Abstract
To explore metabolism mechanism of paeoniflorin in the liver and further understand intact metabolism process of paeoniflorin, a rapid, convenient and effective assay is described using ultra-performance liquid chromatography coupled with hybrid quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS/MS). The strategy was confirmed in the following primary processes: firstly, different concentration of paeoniflorin, rat liver microsomes, coenzymes and different incubated conditions were optimized to build a biotransformation model of rat liver microsomes in vitro by high performance liquid chromatography with diode array detection (HPLC-DAD); secondly, the metabolites of paeoniflorin in rat liver microsomes were detected and screened using UPLC-Q-TOF-MS/MS by comparing the total ion chromatogram (TIC) of the experimental group with those of control groups; finally, the molecular formulae and corresponding chemical structures of paeoniflorin metabolites were identified by comparing the MS and MS/MS spectra with the self-constructed database and simulation software. Based on this analytical strategy, 20 metabolites of paeoniflorin were found and 6 metabolites (including four new compounds) were tentatively identified. It was shown that hydrolysis and oxidation were the major metabolic pathways of paeoniflorin in rat liver microsomes, and the main metabolic sites were the structures of pinane and the ester bond. These findings were significant for a better understanding of the metabolism of paeoniflorin in rat liver microsomes and the proposed metabolic pathways of paeoniflorin might provide fundamental support for the further research in the pharmacological mechanism of Paeoniae Radix Rubra (PRR).
Highlights
Paeoniflorin, a bioactive monoterpene glucoside in the root of Paeoniae Radix Rubra (PRR), has numerous pharmacological effects such as antioxidant [1], anti-inflammatory [2], analgesic [3] and muscle relaxant [4]
The liver is regarded as the essential site for drug biotransformation on account of the large number and high abundance of drug-metabolizing enzymes especially cytochrome P450 (CYP450) which could catalyse some reactions like hydrolysis, oxidation and conjunction [11,12]
Paeoniflorin was purchased from the National Institute for the Control of Pharmaceutical and Biological Products (Beijing, China; catalogue number: 110736) and its chemical structure is shown in figure 1
Summary
Paeoniflorin, a bioactive monoterpene glucoside in the root of Paeoniae Radix Rubra (PRR), has numerous pharmacological effects such as antioxidant [1], anti-inflammatory [2], analgesic [3] and muscle relaxant [4]. Few studies on metabolites of paeoniflorin in vitro especially in liver microsomes have been reported. The metabolic model consisting of liver microsomes and coenzymes is applied for the metabolic study in vitro due to its powerful capability [13,14,15] with the same temperature and physiological environment in vivo [16]. High-resolution mass spectrometry (HRMS) such as hybrid quadrupole time-of-flight mass spectrometry (Q-TOF) analyser is applied to identify the metabolites because of its high-throughput and sensitive analytical technique [17,18].
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