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Abstract (+)-usnic acid (UA) is an active natural phenolic acid ingredient originating from Chinese traditional Tibetan herb. Usnea acid is expected to become a new agent for anticancer and remarkable antitumor. To reveal its metabolic profile, metabolites identification of UA in vivo was studied using ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS/MS) in this present study. The chromatographic separation was performed on a C 18 column with a mobile phase consisted of methanol and water with a flow rate of 0.4 ml/min. The mass spectral analysis conducted in a negative electrospray ionization mode combined with information-dependent acquirement technology (IDA) was used to trace all the potential UA metabolites. Several sensitive and specific multiple data-mining techniques especially key product ions (KPIs) filter were applied to hunt and identify metabolites rapidly. As a result, a total of 36 metabolites were detected after oral administration of UA, including 33, 8 and 16 in rat urine, plasma and bile, respectively. These results showed that the probable metabolite pathways of UA were oxidation, reduction, dihydroxylation, glycine conjugation, glucuronide conjugation, N -acetylcysteine conjugation and methylation. It is the first time to elucidate the profile of UA in vivo. These results not only provided the basis of UA pharmacological properties, but also gave the guidance in clinical medication. Moreover, the analysis strategy and methodology proposed in this paper could be widely used in characterization of other phenolic acids metabolites. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance:: Abelmoschus manihot (L.) Medik. var. manihot is one of the most commonly used Chinese medicines and has played an important role in treating chronic glomerulonephritis and diabetic nephropathy. Aim of the study:: Metabolites identification of traditional Chinese medicine (TCM) is a complex and time-consuming process due to the complicity of TCM and subsequent large number of detected ions. In this paper, UPLC–MS combined with pattern recognition analysis approach were used to simplify and quicken the identification of the metabolites of Abelmoschus Manihot. Materials and methods:: Rat urine samples were collected before (as control sample) and after Abelmoschus Manihot administration. Pattern recognition analysis method was used to differentiate components between Abelmoschus Manihot-treated group and its controlled comparison. These components could be considered as Abelmoschus Manihot-related metabolites in vivo. Results:: LC–MS based metabolomics could be an advanced tool to help us find metabolites with regards to its capacity of processing large datasets, differentiating and classifying of sample groups, as well as its indiscriminative nature of biomarker and metabolite identification. Using this method, seven metabolites were identified, which are flavonoid aglycone glucuronidation, sulfatation, and methylation metabolites. Conclusion:: Our results showed that UPLC–MS based- pattern recognition analysis approach can be used to quickly identify Abelmoschus Manihot related metabolites in biological fluids. Furthermore, this work demonstrates the potential application of combining the UPLC–MS approach with the metabolomics approach in identifying the metabolites of TCM. [Copyright &y& Elsevier]

Abstract: Arctiin, an important lignan compound in Fructus Arctii, has been reported to possess various kinds of bioactivities. Previous studies on the pharmacokinetic of arctiin after oral administration showed that it had a rapid absorption phase followed by a sharp but lasting disappearance. To gain deep insight into the action mechanism of arctiin, the excretion and metabolism of arctiin in vivo should be further studied. In this paper, three metabolites were isolated and identified in rat feces as (−)-enterolactone (M-1), (−)-arctigenin (M-2) and [(2R,3R)-2-(3′-hydroxybenzyl)-3-(3″,4″-dimethoxybenzyl)-butyrolactone] (M-3). Based on the structures of three metabolites, possible metabolic pathways of arctiin in rats are proposed. At the same time, the cumulative excretion rate of arctiin and its metabolites in rat urine and feces were determined, indicating that arctiin was excreted 19.84% in urine and 1.80% in feces, respectively, enterolactone, the most main metabolite, was excreted 35.80% in feces. These results provide very important information for understanding the metabolism and excretion of arctiin in vivo and speculating its action mechanism, they can provide useful information and reference for further metabolic investigations on arctiin in humans. [Copyright &y& Elsevier]

Abstract: Ethnopharmacological relevance: Traditional Chinese medicine (TCM) has been used in clinical practice for several thousand years. TCM has played an indispensable role in the prevention and treatment of diseases, especially the complicated and chronic ones. Pharmacokinetic study on active constituents in herbal preparations is a good way for us to explain and predict a variety of events related to the efficacy and toxicity of TCM. Aim of the study: A selective and sensitive HPLC–MS/MS method was first developed and validated for the determination of luteolin, kaempferol, apigenin, quercetol, and isorhamnetin in rat plasma. Materials and methods: The LC system consisted of an Agilent Technologies Series 1200 system (Agilent, USA) equipped with an automatic degasser, a quaternary pump, and an autosampler. Chromatographic separations were performed on a Waters SunFire™ C18 column (150mm×4.6mm, 5μm), and the column temperature was maintained at 25°C and the sample injection volume was 20μL. The current LC–MS/MS assay was validated for linearity, intra-day and inter-day precisions, accuracy, extraction recovery and stability. Results: The validated method was successfully applied to monitoring the concentrations and pharmacokinetic studies of five flavone compounds in rat plasma after a single oral administration of Verbena officinalis L. extract with a dosage of 8.0mL/kg. The time to reach the maximum plasma concentration (T max1) was 0.48±2.14h for luteolin, 0.25±0.13h for kaempferol, 0.97±1.08h for apigenin, 1.04±4.25h for quercetol and 0.25±0.16h for isorhamnetin, and the maximum plasma concentration (T max2) was 3.97±1.48h, 4.05±0.46h, 4.33±0.58h, 2.99±0.48h and 4.02±0.34h. The elimination half-time (t 1/2) of luteolin, kaempferol, apigenin, quercetol and isorhamnetin was 4.02±0.81, 7.65±0.71, 3.30±0.83, 4.55±0.49 and 5.56±1.32h, respectively. Conclusions: This paper described a simple, sensitive and validated LC–MS/MS method for simultaneous determination of luteolin, kaempferol, apigenin, quercetol and isorhamnetin in rat plasma after oral administration of V. officinalis L. extract, and investigated on their pharmacokinetic studies as well, with a short run time of 5min. [Copyright &y& Elsevier]

Abstract: In this paper, microdialysis combined with ultra performance liquid chromatography/mass spectrometry (UPLC-MS) was applied for the determination of ligustilide in freely moving rats'' brain. The extracellular unbound ligustilide could be detected in rat brain within the first time interval (0–20min) after nasal administration but not after oral administration. This result showed that ligustilide could quickly enter the brain after nasal administration; which implied that ligustilide may have a rapid onset of action. This work demonstrated the potential application of microdialysis combined with UPLC-MS in pharmacokinetic studies. Furthermore, the advantage that fewer animals used in the microdialysis experiment was confirmed. [Copyright &y& Elsevier]

Backgrounds: The dried rhizome of Ligusticum sinense Oliv.cv. Chaxiong has been used to treat cardiovascular and cerebrovascular diseases, atherosclerosis, anemia and stroke. A high purity extract from chaxiong (VOC, brownish yellow oil) was extracted and separated. Its main components were senkyunolide A (SA, 33.81%), N-butylphthalide (NBP, 1.38%), Neocnidilide (NOL, 16.53%), Z-ligustilide (ZL, 38.36%), and butenyl phthalide (BP, 2.48%), respectively. Little is known about the pharmacokinetics of these phthalides in Chaxiong, and different preparations to improve the physicochemistry and pharmacokinetics of VOC have not been investigated. Methods: At different predetermined time points after oral administration or intravenous administration, the concentrations of SA, NBP, NOL, ZL and BP in the rat plasma were determined using LC-MS/MS, and the main PK parameters were investigated. VOC-P188 solid dispersion and VOC-β-CD inclusion compound were prepared by melting solvent method and grinding method, respectively. Moreover, the physicochemical properties, dissolution and pharmacokinetics of VOC-P188 solid dispersion and VOC-β-CD inclusion compound in rats were assessed in comparison to VOC. Results: The absorptions of SA, NBP, NOL, ZL and BP in VOC were rapid after oral administration, and the absolute bioavailability was less than 25%. After the two preparations were prepared, dissolution rate was improved at pH 5.8 phosphate buffer solution. Comparing VOC and physical mixture with the solid dispersion and inclusion compound, it was observed differences occurred in the chemical composition, thermal stability, and morphology. Both VOC-P188 solid dispersion and VOC-β-CD inclusion compound had a significantly higher AUC and longer MRT in comparison with VOC. Conclusion: SA, NBP, NOL, ZL and BP in VOC from chaxiong possessed poor absolute oral bioavailability. Both VOC-P188 solid dispersion and VOC-β-CD inclusion compound could be prospective means for improving oral bioavailability of SA, NBP, NOL, ZL and BP in VOC. [ABSTRACT FROM AUTHOR]

Polygonum capitatum has unique curative effects on the urinary system. In fact, many Polygonum capitatum-based preparations are currently used in the clinic. In China, the combination of levofloxacin (LVFX) with a Chinese herbal preparation derived from Polygonum capitatum has been used for the clinical treatment of urinary system diseases, which can improve the curative effects and reduce the side effects of LVFX. However, the herb-drug interaction (HDI) between these drugs has not been reported and the effect of Polygonum capitatum on the in vivo process of LVFX is unclear. In this article, a sensitive ultraperformance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS) method was developed to evaluate the effects of the combined application of LVFX and the Polygonum capitatum extract on tissue distribution and excretion. Thereafter, the method was validated for selectivity, accuracy, precision, linearity, lower limit of quantification (LLOQ), dilution integrity, recovery, and matrix effect. Based on tissue distribution, LVFX could diffuse into all of the tested tissues, with significant differences in the content of each tissue between the coadministration group and single administration group. At 48 h after the combination was orally administered, the urinary cumulative excretion of LVFX decreased from 20.69% to 11.84% while its fecal cumulative excretion decreased from 26.08% to 13.28%. Our results suggest that a drug interaction exists between the two drugs in the process of distribution and excretion. This study provides important experimental evidence for further studies on the clinical efficacy and mechanism of the Polygonum capitatum extract and LVFX. [ABSTRACT FROM AUTHOR]