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This paper aims to study the difference in the intestinal absorption kinetics of main active components of Sini decoction and its separated recipes and explain the scientificity and rationality of the compatibility of Sini Decoction. A in situ intestinal perfusion rat model was established to evaluate the differences in the absorption of benzoylmesaconine, benzoylaconine, benzoylhypacoitine, mesaconitine, hypaconitine, glycyrrhizic acid, liquiritin and 6-gingerol from Sini Decoction and its separated recipes in the duodenum, jejunum and ileum by high performance liquid chromatography(HPLC). The results indicated that the Sini Decoction group was superior to the Aconiti Lateralis Radix Praeparata group in terms of absorption degree and rate for aconitum alkaloids. The absorption of benzoylmesaconine and hypaconitine in the duodenum, jejunum and ileum was faster and stronger in the Sini Decoction group(Plt;0.05). The absorption degree of glycyrrhizic acid in the duodenum was significantly higher in the Sini Decoction group than in the Glycyrrhizae Radix et Rhizoma group and the Glycyrrhizae Radix et Rhizoma-Zingiberis Rhizoma group(Plt;0.05). The absorption rate and degree of 6-gingerol in the ileum in the Sini Decoction group were significantly higher than those in the Zingiberis Rhizoma group(Plt;0.05). In short, Zingiberis Rhizoma and Glycyrrhizae Radix et Rhizoma can promote the absorption of aconitum alkaloids in different intestinal segments, which reflects the scientific composition of Sini Decoction.

To prepare and evaluate a new formulation of thermosensitive and ion-sensitiveFormulation ofThe phase transition temperature of the gel was optimized to be 36 ℃. The release of baicalin from the gel showed obvious features of sustained release, which accorded well the zero-order kinetics equation. The results of experiments with the rat dry yeast fever model and the mouse xylene auricle swelling inflammation model showed that the gel had significant antipyretic and anti-inflammatory effects that were significantly better than those of the groups treated with the blank gel base and theThe

Based on metabolomics,the effect of Magnolia officinalis before and after " sweating" on gastrointestinal motility disorder( rat) was compared. To study the mechanism of M. officinalis " sweating" increased the efficacy and reduced the toxicity. The rat model of gastrointestinal motility disorder was established by intraperitoneal injection of L-arginine. Pharmacodynamic indexes were relative residual rate of gastric pigment and intestinal propulsion ratio in rats. LC-MS metabolomics and multivariate statistical analysis were used to screen and identify biomarkers associated with gastrointestinal motility disorders,and MetPA database was used to analyze related metabolic pathways. The results showed that M. officinalis could improve gastrointestinal motility disorder whether it " sweating" or not,and the effect of " sweating" M. officinalis was stronger than that of " no sweating" M. officinalis. The metabolites of the experimental groups could be distinguished distinctly,and 15 different compounds and 17 related pathways were identified preliminarily. The mechanism of M. officinalis might be to improve gastrointestinal motility disorder by increasing the content of L-glutamate in the metabolic pathway of alanine,aspartate and glutamate and protecting gastrointestinal barrier. Before " sweating",M. officinalis could reduce taurine through metabolism of taurine and taurine and biosynthetic pathway of primary bile acid,increase the content of deoxycholic acid in glycine goose,and increase the risk of liver and kidney injury. After " sweating",M. officinalis could enhance gastrointestinal motility by increasing the contents of L-tryptophan and serotonin in the tryptophan pathway,and avoid the production of harmful metabolites to achieve synergistic and detoxifying effect.

Ethnopharmacological relevance The dried fruit of Terminalia chebula (fructus chebulae) is an important Traditional Medicine used for intestinal and hepatic detoxification. Gurigumu-7 which is made of fructus chebulae and 6 other traditional medicines is one of the most frequently used compound Mongolian and Tibet medicines for liver diseases. Terminalia phenolics are considered as the bioactive constituents of fructus chebulae and consequently of Gurigumu-7. Aim of the study To compare the pharmacokinetic profiles of Terminalia phenolics after intragastric administration of the aqueous extracts of fructus chebulae and Gurigumu-7 and to evaluate the possible influence of intestinal bacterial metabolism on these pharmacokinetic profiles. Materials and methods An ultra performance liquid chromatography with triple quadrupole mass spectrometry method was established and validated for simultaneously determining the pharmacokinetic profiles of seven Terminalia phenolics after intragastric administration of pure compounds, fructus chebulae extract, and Gurigumu-7 extract. In vitro rat fecal lysates experiments were carried out to explore the metabolic discrepancy between fructus chebulae and Gurigumu-7. Results Seven Terminalia phenolics were detected in rat plasma after intragastric administration of the aqueous extracts of fructus chebulae and Gurigumu-7. Administration of Gurigumu-7 could promote the absorption and increase the Cmax and AUC values of these phenolic constituents compared to fructus chebulae administration. The fecal lysates studies showed that the Terminalia phenolics in Gurigumu-7 were less rapidly bio-transformed than those in fructus chebulae. This may be a contributing factor to the pharmacokinetic discrepancy between the phenolics in fructus chebulae and Gurigumu-7. Conclusion Administration of Gurigumu-7 could increase the absorption of Terminalia phenolics through slowing down the intestinal bacteria metabolism. These results provide, in part, an in vivo rationale for the formulation of the traditional Mongolia / Tibet medicine, Gurigumu-7.

Baicalin (BG) and its aglycone, baicalein (B) are strong antioxidants that exert various pharmacological actions and show unique metabolic fates in the rat. The aim of the present study was to identify major metabolite(s) besides BG in rat plasma after oral administration of BG or B. The main metabolite was detected by HPLC equipped with an electrochemical detector at a potential of +500 mV and identified as baicalein 6-O-β-D-glucopyranuronoside (B6G) by HPLC/MS/MS. When BG at a dose of 20 mg/kg was administered orally to Wistar rats, the level of B6G in plasma was higher than that of BG. Cmax and the area under the concentration-curve from 0 to 24 h (AUC0-24 h) values of the plasma B6G were 1.66 ± 0.34 µM and 19.8 3.9 ± µM · h, respectively, whereas those of BG were 0.853 ± 0.065 µM and 10.0 ± 3.1 µM · h, respectively. When B was administered, similar results were also obtained. B6G-producing activities from B were found in microsomes of both rat jejunum and liver, in spite of the low activity. Rat everted jejunal sacs formed B6G after application of B, but only in a small amount that was excreted into the mucosal side, and not the serosal side, indicating little contribution to the appearance of B6G in plasma. On the other hand, when B was injected into the rat portal vein, B6G was detected at a higher level than BG in the systemic circulation, demonstrating the hepatic contribution to the appearance of plasma B6G.

The alkaloid, rhynchophylline (RHY), from the stems and hooks of Uncaria rhynchophylla was revealed in recent years to have protective effect on neuronal damage. The present research was carried out to investigate the in vivo metabolism of this bioactive alkaloid. After administering RHY to rats, LC-MS detected RHY in plasma, bile, brain, urine and feces, the glucuronides, 11-hydroxyrhynchophylline 11-O-beta-D-glucuronide (M1) and 10-hydroxyrhynchophylline 10-O-beta-D-glucuronide (M2) in bile, and 11-hydroxyrhynchophylline (M3) and 10-hydroxyrhynchophylline (M4) in urine and feces. Within 24 h, 78.0% of RHY was excreted into the feces and 12.6% into the urine of rats after oral administration of 37.5 mg/kg. Monitoring by LC-MS showed that 9.4% of RHY was metabolized to M3 and M4 in a ratio of about 1 : 1. RHY was also detected in the brain (0.650 ng/g) at 3 h after oral administration of the same dose. Cytochrome P450 (CYP) in rat liver microsomes played a key role in RHY hydroxylation. Specific inhibition of CYP isozymes indicated that CYP2D, CYP1A1/2 and CYP2C participated in RHY hydroxylation, but not CYP3A.

Hypoxic pulmonary vascular structural remodeling (HPVSR) is the important pathologic basis of hypoxic pulmonary hypertension (HPH). The discoveries of endogenous gaseous messenger molecules, nitric oxide (NO) and carbon monoxide (CO), have been moving the research of HPVSR to a very new phase. But the effect and significance of heme oxygenase (HO)/CO on the development of HPVSR have not been fully understood. In this study, we observed the alteration of endogenous HO/CO system in five time points during 14 days and found that the content of CO in lung homogenates in rats with HPVSR increased in a time-dependent double-peak manner. Exogenous supply of ZnPP-IX, an inhibitor of HO-1, decreased the content of CO in lung homogenate, decreased the expression of Fas and apoptotic cells in pulmonary artery smooth muscle cells (PASMCs), up-regulated the expression of PCNA in PASMCs, and worsened HPH and HPVSR of hypoxic rats. Meanwhile, exogenous supply of CO played an adverse action. The results showed that the up-regulation of HO/CO exerted a protective role in the development of HPVSR.

One purpose of the present study was to investigate the uptake characteristics of pinocembrin (PCB) and its effect on p-glycoprotein (P-gp) at the blood-brain barrier (BBB). Cultured rat brain microvascular endothelial cells (rBMECs) were used as an in vitro BBB model. Experiments were conducted to examine time-, concentration-, and temperature-dependent elements of PCB uptake, and the effect of classical P-gp inhibitors, cyclosporin A (CsA) and verapamil (Ver), on the steady-state uptake of PCB. Uptake of rhodamine 123 (Rho123), the typical P-gp substance, was measured with or without PCB. Meanwhile, the protein level of P-gp after incubation with PCB was detected by Western blot assay. The results demonstrated that PCB uptake by rBMECs was in a time- and concentration-dependent manner. CsA and Ver slightly increased PCB steady-state uptake by less than 10% (p>0.05). Similar results were observed in Rho123 uptake by co-administration of PCB. Further results were obtained by Western blot assay. PCB might not affect P-gp expression in rBMECs. Overall, the findings demonstrate that the passive transport process may be the main process for PCB to pass through the BBB, and P-gp is likely to have a little effect on the PCB transport process. Furthermore, PCB may not affect the functional activity and the protein expression of the P-gp transporter at the BBB.

The aim of this study was to design and develop a simple in vitro blood-brain barrier (BBB) permeation model for elementarily and rapidly predicting the permeability of candidate compounds at BBB and further evaluating whether P-glycoprotein (P-gp) affects them across BBB. The model was mainly composed of cultured rat brain microvascular endothelial cells (rBMECs), glass contraption, and micropore membrane. First, we evaluated the model by morphological observation. Second, the restriction effects of paracellular transport were verified by measuring marker probes transport, and monitoring transendothelial electrical resistance (TEER) and leakage. Finally, protein expression and activity of P-gp were confirmed by carrying out Western blot analysis and polarized transport of rhodamine-123 (Rho123) in rBMECs. The rBMECs retained both endothelial cells and BBB features. The rBMECs model reproducibly attained approximately 130 Ω cm² on the steady-state TEER value, and displayed a barrier function to marker probes transport by decreasing the permeability. Protein band of 170 kDa manifested the existence of P-gp in the rBMECs, and the findings of cyclosporin A-sensitive decrease of Rho123 efflux confirmed the presence of P-gp activity. A simple, rapid, and convenient in vitro BBB permeation model was successfully established and applied to evaluate the BBB transport profiles of three natural flavonoids: quercetin, naringenin, and rutin.

PURPOSE This paper investigates the metabolic fate of isorhynchophylline (ISOR) as a main bioactive oxindole alkaloid in the traditional Chinese medicine. METHODS After oral administration of ISOR to rats, plasma, bile, urine and feces were analyzed by LC-MS. Hydroxylation of ISOR and successive glucuronidation proceeded in vitro by incubation with rat liver microsomes. RESULTS ISOR was identified in plasma, 11-hydroxyisorhynchophylline 11-O--D-glucuronide (MI1) and 10-hydroxyisorhynchophylline 10-O--D-glucuronide (MI2) in bile, and free 11-hydroxyisorhynchophylline (MI3) and 10-hydroxyisorhynchophylline (MI4) in urine and feces. Within 24 h, 71.6% of ISOR was excreted into the feces (in 20.0 g) and 13.8% into the urine (in 20.0 ml) of rats after oral administration of 37.5 mg/kg. Monitoring by LC-MS showed that 8.5% of ISOR was metabolized to MI3 and MI4 in a ratio of ca. 1:1. Specific inhibition of CYP isozymes indicated that CYP2D, CYP1A1/2 and CYP2C participate in ISOR hydroxylation. CONCLUSIONS ISOR was involved in the circulatory system after oral administration. Cytochrome P450 (CYP) in rat liver microsomes played a key role in ISOR hydroxylation.

The metabolism of ganoderiol F (GF), a cytotoxic and antitumor triterpene from Ganoderma lucidum, by intestinal bacteria and its pharmacokinetics in rats were investigated by using liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS). GF was converted to ganodermatriol by anaerobic incubation with bacterial mixtures from rats and humans. This metabolite was detected in rat feces, but not in plasma and urine, after oral administration of GF. The fate of GF after oral (p.o.) and intravenous (i.v.) administration to rats was examined in pharmacokinetics studies. Plasma samples pretreated by solid-phase extraction were quantified by HPLC/MS/MS over a GF concentration range of 1.25-100 ng/ml (S/N = 5). The intra- and interday precision (CV%) was below 8% and accuracy was within the range of 95.9-103.6% for all samples. The range of recovery ratios was 89.2-98.2%. After the administration of GF at 0.5 mg/kg i.v., the plasma concentrations of GF quickly declined and the elimination half-life values (t(1/2alpha) and t(1/2beta)) were about 2.4 and 34.8 min. On the other hand, the elimination half-life values (t(1/2alpha)) after p.o. administration of GF at doses of 20 and 50 mg/kg were 14.4 and 143.3 min for the former, and 18.6 and 114.6 min for the latter. The AUC(0-t) value was 11.17 (ng/ml) h at a GF dose of 0.5 mg/kg i.v., but 49.4 and 111.6 (ng/ml) h at GF doses of 20 and 50 mg/kg p.o., respectively, indicating that the AUC(0-t) value is proportional to the administered oral doses. The estimated absolute bioavailability of GF in rats was F = 0.105.

Ergosterol peroxide (EPO, 1) is a major antitumor sterol produced by edible or medicinal mushrooms. Following oral administration of 1 to rats or anaerobic in vitro incubation of 1 with rat fecal bacteria, three metabolites were detected and their structures were identified to be 5alpha,6alpha-epoxyergosta-8(14),22-diene-3beta,7alpha-diol (M1, 2), 5alpha,6alpha-epoxyergosta-8,22-diene-3beta,7alpha-diol (M2, 3), and 5alpha,6alpha-epoxy-3beta-hydroxyergosta-22-ene-7-one (M3, 4) by spectroscopic analysis. Of these, M2 and M3 showed more potent inhibitory activity than the original compound 1 against proliferation of CACO-2, WiDr, DLD-1 and Colo320 human colorectal adenocarcinoma cells. These findings suggest that bacterial metabolites of EPO play a significant role in its cytotoxic activity against human colorectal cancer cells.