Dan Li,Zhonglian Cao,Xueling Liao,Ping Yang,Li Liu
Paclitaxel is a broad-spectrum anti-cancer drug by targeting microtubulin. However, multidrug resistant (MDR) makes its clinical application more difficult and results in failure of chemotherapy. Tetrandrine as a potential multidrug resistant modulator could be combined with other anti-cancer drugs. In this study, ultra-performance liquid chromatography (UHPLC) combined with quadrupole time-of-flight mass spectrometry (QTOF) was applied to simultaneously qualitative and quantitative analysis of paclitaxel for the pharmacokinetic studies while combined with tetrandrine. This method was developed based on non-target screening mode IDA (Information Dependent Acquisition). As a result, the validated range was 0.25–64 ng/ml (30 µl plasma) for paclitaxel. Totally 33 metabolites of paclitaxel and tetrandine were identified in vivo and in vitro. The main metabolites of PTX were dose-dependent decreased with different amounts of tetrandine co-administration no matter in vivo and in vitro, the exposure of PTX increased in pharmacokinetic study. The verified method is sensitive accurate and effective for the simultaneous determination of paclitaxel and its metabolites in blood, urine and live microsome incubation samples and it was successfully applied to evaluate the pharmacokinetics and drug–drug interaction between paclitaxel and tetrandine. Furthermore, a biosensor technology, surface plasmon resonance (SPR) analysis was applied to preliminary evaluate the competitive protein binding of multiple components. The SPR analysis indicated that the affinity between 6-hydroxy-paclitaxel and micotubulin is similar to that between paclitaxel and micotubulin, and tetrandrine also does not form a competitive combination with paclitaxel. For human, 6-hydroxy-paclitaxel is the one of main metabolites of paclitaxel, so the results suggested that tetrandine has an influence on the metabolite of paclitaxel, but tetrandine and the main metabolites of PTX probably do not affect PTX's biological targeting, the effect of its pharmacological action needs to be further studied.
Jun Li,Ming Li,Ke Ye,Qixin Jiang,Mi Wang,Xiaodong Wen,Jie Yang
Ethnopharmacological relevance Xian-He-Cao-Chang-Yan formula (XHCF) is consisting of six crude drugs including Agrimoniae Herba, Coptidis Rhizoma , Aucklandiae Radix, Cicadae Periostracum, Acori Tatarinowii Rhizoma, and Platycodonis Radix at the ratio of 5:1.5:1.5:1.5:1.5:1. It has been used to improve syndromes of ulcerative colitis (UC) for many years. Aim of the study This study was designed to study the bioactive ingredients and therapeutic mechanisms of XHCF. Materials and methods The chemical profile of XHCF was characterized by UHPLC-QTOF-MS/MS. The effects and mechanisms of XHCF on UC were investigated in colitis mice induced by dextran sulfate sodium (DSS) and LPS-stimulated RAW 264.7 cells. Results A total of 103 compounds were characterized in XHCF. XHCF could effectively improve acute colitis induced by DSS. More importantly, XHCF significantly decreased M1 macrophage markers (CD11c, IL-6 and IL-1β) whereas increased M2 macrophage markers (CD206) in colitis mice, suggesting it could regulate macrophage polarization. Furthermore, the levels of HK2 and lactic acid in colon tissues were significantly reduced by XHCF, indicating that XHCF could inhibit glycolysis. It also down-regulated HK2 expression in macrophages challenged by LPS. In addition, XHCF enhanced the phosphorylation of AMPK both in vivo and in vitro , suggesting the involvement of AMPK in XHCF function. Conclusions XHCF ameliorated DSS-induced colitis in mice via inhibition of M1 macrophage polarization, probably by the modulation of macrophage metabolic reprogramming via AMPK, contributing to its anti-inflammatory activity. The synergistic actions of multiple ingredients might be responsible for the therapeutic benefits of XHCF on UC.
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