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Ethnopharmacological relevance Metabolomics is the comprehensive assessment of endogenous metabolites of a biological system in a holistic context, and its property consists with the global view of Traditional Chinese Medicine (TCM). Shuihonghuazi Formula (SHHZF) has been used for liver cancer early treatment in clinical for more than thirty years, but its mechanism remains unclear completely. This paper was designed to explore the therapeutic effects of SHHZF on liver cancer and its metabolomic characters. Materials and methods All the rats were given diethylnitrosamine (DEN) at the dosage of 70 mg/kg for 14 weeks. From the 7th weeks, SHHZF was given to the rats which lasted for 10 weeks. Therapeutic effects of SHHZF was compared with that of cyclophosphamide (CTX). High performance liquid-chromatography/electrospray-ionization time of flight mass spectrometer (HPLC/ESI-TOF-MS) combined with pattern recognition approaches including principal component analysis (PCA), partial least squares-discriminant analysis (PLS-DA), was integrated to approximate the comprehensive metabolic signature and discover differentiating metabolites by Agilent MPP 12.1. The changes in metabolic profiling in plasma were restored to their baseline values after SHHZF treatment according to the PLS-DA score plots. Results The results indicated that 23 ions as “differentiating metabolites”. The alterations in those metabolites were associated with perturbations in fatty acid and bile acid metabolism, in response to liver cancer through immune and nervous system. And SHHZF could increase the uptake and utilization of linoleic acid and oleic acid, increase arachidonic acid-like substance content and enhance organism immunity of liver cancer rats. And it also could increase the translation from phosphatidylethanolamine (PE) to phosphatidylcholine (PC), linoleic acid metabolism and inhibits abnormal metabolism of bile acid. Conclusions The mechanism of therapeutic effects of SHHZF on liver cancer by adjusting the activities of PE N-methyl transferase (PEMT), Lysophospholipase D, methylenetetrahydrofolate reductase (MTHFR) and lysophospholipase was elucidated by the method of metabonomics for the first time. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Frankincense (FRA), Ruxiang, is the resin of Boswellia carterii Birdw and Boswellia bhaw-dajiana Birdw which has been used for centuries as formulas to improve the circulation and to relieve pain against carbuncles. Stir-fried Frankincense (SFF) and vinegar processed Frankincense (VPF) are two major processed Frankincense, and the processing procedures reportedly enhance the curative efficacy or reduce the side effects of FRA. This paper describes the comparisons in plasma pharmacokinetic behaviors of 11-keto-β-boswellic acid (KBA) and 3-acetyl-11-keto-β-boswellic acid (AKBA) in FRA and its processed products, and their effects on coagulation factors and blood clotting tetrachoric, using an acute cold blood-stasis animal model after oral administration of FRA, SFF, and VPF. Materials and methods For pharmacokinetic study, Sprague–Dawley (SD) rats were randomly divided into three groups, including group FRA, group SFF and group VPF. And the plasma samples were analyzed by HPLC. For study of anticoagulatory effect, SD rats were randomly divided into six groups, including control, acute cold blood-stasis model, Fu-fang-dan-shen tablet- (0.75 g/kg), FRA-, SFF-, and VPF-treated (2.7 g/kg) groups, respectively. The serum contents of thrombin–antithrombin complex (TAT), D-dimer (D-D), and prostacyclin (PGI 2 ) of each group were measured by ELISA. The values of prothrombin time (PT), thrombin time (TT), activated partial thromboplastin time (APTT) and fibrinogen (FIB) were also assessed by hematology analyzer. Results Significantly increased levels of C max , AUC, T 1/2, and MRT were found in rats treated with the processed products. In addition, decreased levels of D-D and TAT and increased contents of PGI 2 were observed in rats given FRA and its processed products, compared with that of the model group. Moreover, VPF improved anticoagulation more than SFF in the animals. Conclusions The observed improvement of anticoagulation by processed FRA may result from the increased absorption and bioavailability of triterpenoids. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Sandpaper [ Ficus exasperata Vahl (Moraceae)] leaf has been reportedly used in folklore for the management/treatment of cardiovascular diseases with little/or no scientific basis for their action. This study sought to investigate the effect of dietary supplementation of sandpaper leaf on angiotensin-I converting enzyme (ACE) activity in hypercholesterolemia as well as the effect of their phenolic extract on this enzyme in vitro . Materials and methods The phenolic extract was prepared, then, the inhibitory effect of the leaf extract on ACE was determined in vitro . Thereafter, the effect of dietary supplementation of sandpaper leaf on angiotensin-I converting enzyme (ACE) activity in high cholesterol diet fed rats for 14 days was evaluated as well as some biochemical parameters. Results The result revealed that under in vitro condition, the phenolic extract inhibited ACE (IC 50 =14.7 µg/mL) in a dose-dependent manner (0–10 µg/mL). Feeding high cholesterol diets to rats caused a significant ( P <0.05) increase in the ACE activity. However, there was a significant ( P <0.05) decrease in the ACE activity as a result of supplementation with the sand paper leaves. Furthermore, there was a significant ( P <0.05) increase in the plasma lipid profile with a concomitant increase in malondialdehyde (MDA) content in rat liver and heart tissues. However, supplementing the diet with sandpaper leaf (either 10% or 20%) caused a significant ( P <0.05) decrease in the plasma total cholesterol (TC), triglyceride (TG), very low density lipoprotein-cholesterol (VLDL-C), and low-density lipoprotein-cholesterol levels (LDL-C), and in MDA content in the tissues. Conversely, supplementation caused a significant ( P <0.05) increase in plasma high-density lipoprotein-cholesterol level when compared with the control diet. Reversed phase HPLC analysis of the extract revealed Quercitrin (43.7 mg/g), chlorogenic acid (42.8 mg/g) and caffeic acid (33.9 mg/g) as the major phenolics in the leaf. Conclusion The inhibition of ACE activity and prevention of hypercholesterolemia by sandpaper leaf could be part of the possible mechanism underlying its anti-hypertensive property which could lay credence to its use in folk medicine. However, these activities may be directly/indirectly attributed to the polyphenolics present. [ABSTRACT FROM AUTHOR]

Abstract: Aim of the study: This study aimed to develop a specific HPLC–MS method for simultaneous quantification of four flavones of Glycyrrhiza in rat plasma after oral administration and to describe the pharmacokinetics of four flavones in rat plasma. Materials and methods: A simple, sensitive and selective method for simultaneous determination of four flavones of Glycyrrhiza in rat plasma, i.e., liquiritin, isoliquiritin, liquiritigenin, and isoliquiritigenin, by high performance liquid chromatography–tandem mass spectrometry (HPLC–MS) with negative electrospray ionization mode, was developed and validated. The method was applied to investigate the pharmacokinetics of four flavones in rat plasma after oral administration of Glycyrrhiza flavones. Chromatographic separation was accomplished on an Agilent TC-C18 column (4.6mm×250mm, and 5μm), with gradient elution by using a mixture of methanoic acid (A) and acetonitrile (B) as the mobile phase at a flow rate of 0.8mL/min. Results: The calibration curves for four flavones had good linearity higher than 0.997 in the measured range. Relative standard deviations (RSDs) of the intra- and inter-day precision at different levels were all less than 4.8%. The pharmacokinetic profile of four flavones in rat plasma was fitted with a two-compartment model detected by a simple, rapid and accurate HPLC–MS method. Time (h) to reach peak concentration (μg/mL) of liquiritin (2.69±0.04), isoliquiritin (10.16±0.02), liquiritigenin (2.83±0.02), and isoliquiritigenin (0.28±0.01) was 2.02±0.23, 1.97±0.20, 0.48±0.02, and 1.93±0.36, respectively. The distribution and elimination half-life (h) and area under the concentration–time curve (μg/mL–h) from t=0 to last time of liquiritin, isoliquiritin, liquiritigenin, and isoliquiritigenin were 1.02±0.48/2.27±0.53/16.97±0.43, 2.04±1.01/2.38±0.80/69.20±5.24, 0.35±0.10/4.26±0.16/14.83±0.11, and 1.18±0.32/3.04±0.22/2.10±0.09, respectively. Isoliquiritin presented the phenomenon of double peaks and the others appeared together in a single and plateau absorption phase. Isoliquiritigenin had the lowest oral bioavailability because of C max and AUC0−∞. Liquiritigenin had the fastest absorption and distribution rate and the lowest elimination rate according to T max, t 1/2α, and t 1/2β. Conclusions: This paper first reported on identification and determination of four flavones of Glycyrrhiza in rat plasma and their respective pharmacokinetic characteristics. The results provided a meaningful basis for better understanding the absorption mechanism of Glycyrrhiza and evaluating the clinical application of this medicine. [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: Libanotis buchtormensis is the source of an important traditional medicine from Shaanxi province of China used in the treatment of many illnesses. Libanotis buchtormensis supercritical extract (LBSE) has analgesic, sedative and anti-inflammatory qualities. Osthole is one of the major bioactive components of LBSE; it is known for its significant anti-tumor, analgesic, and anti-inflammatory properties, it also alleviates hyperglycemia. Aim of the study: The purpose of the present study was to compare the pharmacokinetics and tissue distribution of osthole in Sprague-Dawley (SD) rats after oral administration of pure osthole and LBSE. The two preparations were administered at the same osthole dose (approximately 130mg/kg). The results should provide some guidance for the clinical applications of Libanotis buchtormensis. Materials and methods: Comparative pharmacokinetics and tissue distribution of osthole in SD rats after oral administration of pure osthole and LBSE were analyzed using reversed-phase high-performance liquid chromatography (RP-HPLC). All pharmacokinetic data were analyzed using 3P97 software. Samples of blood and internal organs (heart, liver, spleen, lungs and kidney) were collected and pretreated according to the experimental schedule. After pretreatment, plasma and tissue samples were extracted using ether–ethyl acetate mixture (3:1, v/v). The concentration of osthole in the plasma and tissues were determined using the RP-HPLC method. Results: The procedure described in this paper shows good precision and stability and is suitable for the osthole assays in biological samples. We found that the average plasma concentration-time profile of osthole after oral administration of osthole and LBSE showed a single peak. There were also clear differences between plasma concentrations of osthole after oral administration of pure osthole and LBSE. Non-osthole ingredients in LBSE showed some pharmacokinetic interactions with osthole and hence decreased its absorption levels (p<0.05). Our results show different tissue distribution of osthole in the single and composite administration regimens. Conclusions: This study compares the pharmacokinetic characteristics and tissue distribution of osthole in rats after oral administration of pure osthole and LBSE; the results might be useful in clinical application of this traditional Chinese herbal medicine. [Copyright &y& Elsevier]

Abstract: It is difficult to develop injectable sustained delivery systems for herbal medicines because of their composition complexity. Encapsulating various compounds with different physiochemical properties and achieving their synchronized and sustained release seem too hard to realize. In this paper, an injectable nanoparticulate system based on an mPEG–PLGA–mPEG (PELGE) platform was prepared for co-encapsulation and sustained release of four active components (ginkgolides A, B, C and bilobalide) in Ginkgo biloba extract. Different carriers were screened by macrophage uptake experiment for their ability to be long-circulation. Drug loaded nanoparticles were prepared with 10% PEG2000 modified PLGA by a co-precipitation method. The encapsulation efficiency of the total ginkgo terpenes (GT) in the optimal formulation was 78.84±2.06% with a loading dose of 11.90±0.31mg/150mg PELGE. The particles exhibited a spherical shape with a mean diameter of 123.3±44.0nm and zeta potential of −30.86±2.49mV. Sustained and synchronized release of the four components from PELGE nanoparticles was observed both in vitro and in vivo, which was mainly contributed to the long circulation of PEGylated nanoparticles and the slow degradation of PLGA. The half-life time of the four terpenoid compounds were also significantly improved by incorporation into PELGE nanoparticles. The results indicate that a PELGE nanoparticle is a promising carrier system for sustained and synchronized release of herbal medicines containing multiple components. [Copyright &y& Elsevier]

Abstract: Ethnopharmacological relevance: Fuzi, which is the processed lateral roots of Aconitum Carmichaeli. Debx and is widely distributed over the southwest provinces of China, is recognised for its anti-inflammatory and analgesic effects. Aim of the study: The pharmacokinetic properties of Fuzi are inadequately understood. Aconitine, the primary highly toxic ingredient of Fuzi, is well known as the target marker of Fuzi. The purpose of the present study is to investigate the pharmacokinetic behaviours of aconitine in vivo following single and multiple administrations of processed Fuzi extracts and to compare the pharmacokinetic characteristics of aconitine after administrations of pure aconitine or Fuzi extracts as well as compare the difference at single dose and multiple doses. The in vitro aconitine protein binding in plasma through equilibrium dialysis was also examined. Methods: A high performance liquid chromatography (HPLC) method was developed for the determination of aconitine in Fuzi crude extracts and a fast ultra performance liquid chromatography-tandem mass spectrometry (UPLC/MS/MS) was developed to investigate the pharmacokinetic behaviour of aconitine as the targeted marker of Fuzi. Results: The absolute bioavailability (F %) after the administration of 0.5mg/kg aconitine and Fuzi extract (0.118mg/kg aconitine) in rat was 8.24±2.52% and 4.72±2.66%, respectively. Aconitine absorption was very fast at the t max 30.08±9.73min for pure aconitine and 58.00±21.68min for Fuzi extract administration. Aconitine was also eliminated rapidly with a short half-life (i.v., 80.98±6.40min) and a low rate of protein bounding (23.9–31.9%). No significance was observed on all the pharmacokinetics parameters following the single and multiple doses of pure aconitine (ANOVA, p >0.05). However, the absorption of aconitine after multiple administrations of Fuzi extract was much faster than that of a single dose (t max: 58.00±21.68 vs. 20.00±8.66min, p <0.05), and the area under the plasma concentration–time curve (AUC) was higher than that of a single dose. Conclusions: The pharmacokinetic behaviour of processed Fuzi was determined in this paper. The aconitine has low bioavailability. No variation in the pharmacokinetic behaviours of pure aconitine was observed after single and multiple administrations. In contrast, multiple administrations of processed Fuzi extract could result in variations in its pharmacokinetic behaviour in AUC and t max indicating that multiple dose might increase the bioavailability of aconitine, which may result in its toxicity. In addition, aconitine has a low protein bounding (23.9–31.9%), resulting in its rapid elimination. [Copyright &y& Elsevier]