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Zhong Zuo

Publications and source records attributed to Zhong Zuo.

At least 19 recordsLinked to original sources
PubMed2006

Involvement of UDP-glucuronosyltransferases in the extensive liver and intestinal first-pass metabolism of flavonoid baicalein.

PURPOSE: The present study aims to investigate the involvement of UDP-glucuronosyltranferase (UGT) in the extensive liver and intestinal first-pass glucuronidation of baicalein (B) in both rats and humans and also to study sulfation and P450 mediated hydroxylation of B. MATERIALS AND METHODS: B was incubated with liver and intestine microsome, cytosol, S9 fractions from human, rat and various human recombinant UGT isozymes, respectively. The generated metabolites were identified by HPLC/MS/MS and quantified by HPLC/UV. RESULTS: Three metabolites of B namely baicalein 7-O-glucuronide (BG), the isomer of baicalein 7-O-glucuronide (BG'), and baicalein sulfate were found. BG, the predominant metabolite of B, was extensively generated in liver and jejunum microsomes in both humans and rats. Its formation was mainly catalyzed by UGT 1A9 and also mediated by UGT 1A1, 1A3, 1A8, 1A7 and 2B15 with different kinetic profiles. UGT 1A8 mediated formation of BG' was mainly found in human intestine and rat liver microsomes. Sulfation and P450 mediated hydroxylation of B were much less significant than glucuronidation. CONCLUSIONS: Extensive liver and intestinal first-pass glucuronidation of B were found in both humans and rats. Under the current experimental conditions, UGT 1A9 and UGT 1A8 demonstrated the fastest formation rate of BG in human liver preparations and BG' in human intestine preparations, respectively.

Algorithms↗
PubMed2006

Evaluation of HO-1-u-1 cell line as an in vitro model for sublingual drug delivery involving passive diffusion--Initial validation studies.

The aim of this study was to provide preliminary validation of a new sublingual mucosal cell line (HO-1-u-1) for use as in vitro sublingual drug delivery screening of compounds involving passive diffusion. HO-1-u-1 cells were seeded on cell culture inserts. The ultrastructure and integrity of cell layers, inter-passage variation and directionality of drug transport, and apparent permeability coefficient (P(app)) of eight beta-blockers (representing compounds involving passive diffusion) were determined. HO-1-u-1 cells grown on inserts formed stratified and epithelial-like structure and maintained the typical histological features of normal human sublingual epithelium. The maximal integrity of the cell layer was reached in 23 days. No significant inter-passage variation was found at the passages ranging from 2 to 11 when measured by radiolabeled transcellular and paracellular markers (testosterone and mannitol, respectively). Bidirectional transport studies confirmed the passive diffusion as the mechanism of transport for these markers. The P(app) of eight beta-blockers across HO-1-u-1 cell culture ranged from 2.89+/-0.17 to 6.37+/-0.37x10(-6)cm/s and correlated well to the P(app) obtained from porcine sublingual mucosa (r(2)=0.647 and 0.83 when excluding propranolol). The above results indicate that the HO-1-u-1 cells grown on inserts may offer as a potentially in vitro model for screening sublingual drug permeation involving passive diffusion.

Administration, Sublingual↗
PubMed2006

Intestinal absorption of hawthorn flavonoids--in vitro, in situ and in vivo correlations.

Our previous studies identified hyperoside (HP), isoquercitrin (IQ) and epicatechin (EC) to be the major active flavonoid components of the hawthorn phenolic extract from hawthorn fruits demonstrating inhibitory effect on in vitro Cu(+2)-mediated low density lipoproteins oxidation. Among these three hawthorn flavonoids, EC was the only one detectable in plasma after the oral administration of hawthorn phenolic extract to rats. The present study aims to investigate the intestinal absorption mechanisms of these three hawthorn flavonoids by in vitro Caco-2 monolayer model, rat in situ intestinal perfusion model and in vivo pharmacokinetics studies in rats. In addition, in order to investigate the effect of the co-occurring components in hawthorn phenolic extract on the intestinal absorption of these three major hawthorn flavonoids, intestinal absorption transport profiles of HP, IQ and EC in forms of individual pure compound, mixture of pure compounds and hawthorn phenolic extract were studied and compared. The observations from in vitro Caco-2 monolayer model and in situ intestinal perfusion model indicated that all three studied hawthorn flavonoids have quite limited permeabilities. EC and IQ demonstrated more extensive metabolism in the rat in situ intestinal perfusion model and in vivo study than in Caco-2 monolayer model. Moreover, results from the Caco-2 monolayer model, rat in situ intestinal perfusion model as well as the in vivo pharmacokinetics studies in rats consistently showed that the co-occurring components in hawthorn phenolic extract might not have significant effect on the intestinal absorption of the three major hawthorn flavonoids studied.

Animals↗
PubMed2006

Improved quality control method for Danshen products--consideration of both hydrophilic and lipophilic active components.

The current study intends to provide an improved quality control analysis for Danshen product-a representative herbal product with known active components that are both hydrophilic and lipophilic in nature. A simple HPLC method with photodiode-array (PDA) ultraviolet detection was developed for the simultaneous determination of three major lipophilic components (cryptotanshinone, tanshinone I and tanshinone IIA) and three major hydrophilic components (danshensu, protocatechuic aldehyde and salvianolic acid B) of Danshen (Salvia miltiorrhiza). These six components were successfully separated using Radial-pak C18 cartridge with the elution gradient consisting of 0.5% acetic acid in water and 0.5% acetic acid in acetonitrile at a flow rate of 1 ml/min. The intra-day and inter-day precisions of the analysis were within 2.32 and 2.0%, respectively. The detection limits were 0.02, 0.01, 0.01, 0.05, 0.005 and 0.02 microg/ml for cryptotanshinone, tanshinone I, tanshinone IIA, danshensu, protocatechuic aldehyde and salvianolic acid B, respectively. The developed method has been applied to the simultaneous determination of above six major components in Fufang Danshen Tablet and Dripping Pill products by extraction with methanol and water. It has been demonstrated that salvianolic acid B and danshensu are the major components among the eight commercial Fufang Danshen products studied. The current developed method with methanol as extraction solvent provides a simple and efficient method for simultaneous detection of both lipophilic and hydrophilic major components in Danshen products.

Chromatography, High Pressure Liquid↗
PubMed2006

Intestinal absorption of Stemona alkaloids in a Caco-2 cell model.

The intestinal absorption of neotuberostemonine and neostenine, two major bioactive alkaloids of the commonly used antitussive traditional Chinese medicine Stemona tuberosa Lour, was investigated using a Caco-2 monolayer model. Both alkaloids exhibited a high absorptive permeability which was higher for neostenine [P(app(AB)) = 12.03 +/- 1.14 x 10 (-6) cm/s] than for neotuberostemonine [P(app(AB)) = 9.27 +/- 0.79 x 10 (-6) cm/s], indicating that they are likely to be well absorbed and orally active. Furthermore, both alkaloids were identified to be the substrates of P-glycoprotein and have a transport preference from the basolateral to apical direction with efflux ratios between 2 and 3. Cyclosporin A dose-dependently inhibited the secretory permeability of these alkaloids and abolished their active efflux transport.

Alkaloids↗
PubMed2006

Effect of the co-occurring components from green tea on the intestinal absorption and disposition of green tea polyphenols in Caco-2 monolayer model.

This study aimed to investigate the effect of co-occurring components from green tea on the intestinal absorption and disposition of green tea polyphenols (GTPs) using the Caco-2 cell monolayer model. The absorption and secretion transport of the four GTPs, in the form of individual pure compounds, pure compound mixtures and green tea extract, were studied in the Caco-2 cell model. Four GTPs and their metabolites were analysed by HPLC/MS and HPLC coupled with electrochemical detector. The apparent permeability coefficients (P(app)) of each compound, as well as the metabolites (mainly sulfation and methylation conjugates) generated, were compared for the different dosing formulations utilized. The results showed that the absorption transport of the four GTPs in different dosing formulations was similar. However, the secretion transport profiles of (-)-epicatechin (EC), (-)-epigallocatechin (EGC) and (-)-epigallocatechin gallate (EGCG) were altered when the GTP mixture was administered. It was suggested that transporter competition resulting in reduced efflux of EC, as well as metabolic competition resulting in reduced formation of EGC sulfate and methylated EGC sulfate, might be involved during the secretion transport of GTP mixture.

Biological Transport↗
PubMed2005

Position preference on glucuronidation of mono-hydroxylflavones in human intestine.

Extensive intestinal glucuronidation has been previously reported in both human and animals after oral administration of naturally occurred flavonoids. The present study aims to investigate the relationship between human intestinal glucuronidation activity and the position of hydroxyl substitution on flavonoids. Seven commercially available mono-hydroxyflavones (HF), namely 3-, 5-, 6-, 7-, 2'-, 3'- and 4'-mono-hydroxyflavones, were chosen as model compounds. Glucuronidation activity of the selected seven HFs was investigated by incubating each HF at various concentrations with human jejunum S9 at 37 degrees C for 10 min. The generated glucuronides were identified by HPLC/MS and quantified by HPLC/UV. Metabolic kinetics parameters including Km and Vmax of each HF were determined. The results demonstrated that the glucuronidation activity of 6- and 3'-mono-hydroxyflavones was much greater than that of 3-, 4'-, 7- and 2'-HF with 5-HF to be the lowest. The findings imply that nucleophilicity and stereo-conformation of OH substituents are crucial for the intestinal glucuronidation of flavonoids.

Biological Availability↗
PubMed2005

Lack of effect of beta-cyclodextrin and its water-soluble derivatives on in vitro drug transport across rat intestinal epithelium.

The present study aimed to investigate whether beta-cyclodetxrin (beta-CD) and its water-soluble derivatives, hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and sulfobutyl ether beta-cyclodextrin (SBE-beta-CD), exert any effects on the permeation of two drug transport markers (propranolol and lucifer yellow) across rat intestinal epithelium. Rat ileum was stripped of its serosa and mounted inside an Ussing Chamber. Apparent permeability coefficients (P(app)) of the markers from the mucosal to serosal side of the tissue were determined at 37 degrees C in the presence and absence of the beta-cyclodextrins on the mucosal side. Potential difference (PD) was constantly monitored during each experiment to ensure maintenance of the viability and integrity of the tissue. Pre-incubation with 1% beta-CD, 1% HP-beta-CD or 1.48% SBE-beta-CD on the mucosal side for 30 min did not significantly alter the PD and the propranolol permeability (p>0.05). Co-incubation with 1% beta-CD or 1% HP-beta-CD exerted no significant effect on the P(app) of both propranolol and lucifer yellow (p>0.05), but co-incubation with 1.48% SBE-beta-CD lowered the P(app) of propranolol from (1.71+/-0.44)x10(-5) to (0.19+/-0.04)x10(-5)cm/s, which may be ascribed to the molecular complexation of propranolol with SBE-beta-CD. All three beta-cyclodextrins exert no apparent impact on both (passive) transcellar and paracellular drug transports.

Adrenergic beta-Antagonists↗
PubMed2005

Role of intestinal first-pass metabolism of baicalein in its absorption process.

PURPOSE: The aim of the present study was to investigate the role of intestinal first-pass metabolism of baicalein (B) in its absorption process. METHODS: The intestinal absorption of B was characterized using Caco-2 cell monolayer model and rat in situ single-pass intestinal perfusion model. In addition, preliminary metabolic kinetics of B was evaluated in both rat and human intestinal S9 fractions. RESULTS: B was well absorbed and extensively metabolized to baicalin (BG), baicalein-7-O-beta-glucuronide, in rat intestinal perfusion model, whereas less extent of metabolism was observed in the Caco-2 cell monolayer model. Moreover, BG generated in the intestinal epithelium during the absorption of B also rapidly transported to both the apical side (the apical chamber of Caco-2 model and the perfusate of the intestinal perfusion model) as well as the basolateral side of the small intestine (the basal chamber of Caco-2 model and the mesenteric vein of the intestinal perfusion model). From the preliminary metabolic studies, it was found that a higher loading dose of B resulted in a less extent of metabolism in intestine. In addition, the extent of metabolism of B was similar in jejunum and ileum when 50 microM of B was perfused through different sections of rat small intestine. CONCLUSION: The first-pass metabolism of B in small intestine may play an important role in its low oral bioavailability.

Animals↗
PubMed2005

Pharmacokinetics and modeling of quercetin and metabolites.

PURPOSE: To determine the pharmacokinetics of quercetin and its glucuronide/sulfate conjugates and to develop a pharmacokinetic model to simultaneously describe their disposition after intravenous and oral administration in rats. METHODS: After oral, intraportal, and intravenous administration of quercetin, serial plasma, urine, and fecal concentrations of quercetin and its conjugates were determined by an HPLC method. Enterohepatic recirculation was evaluated in a linked-rat model as well as after oral administration of bile containing quercetin and its metabolites. Based on the experimental data, a specific compartmental model was developed and validated to describe and predict the plasma concentration-time profiles of quercetin and its conjugates after oral and intravenous administration. RESULTS: Only 5.3% of unchanged quercetin was bioavailable, although the total quercetin absorbed was as high as 59.1%. After oral administration, about 93.3% of quercetin was metabolized in the gut, with only 3.1% metabolized in the liver. No significant enterohepatic recirculation was observed for both quercetin and its conjugated metabolites. The pharmacokinetic model fitted well the observed data of quercetin and its conjugates. CONCLUSIONS: Our study clarifies the relative importance of the gut, liver, and bile in the metabolism and excretion of quercetin and its conjugates. The pharmacokinetic model appears to be suitable for describing the absorption and disposition of the quercetin and its conjugates and may be applicable to other flavonoids that undergo similar pharmacokinetic pathways.

Administration, Oral↗
PubMed2005

Physicochemical and structural characterization of quercetin-beta-cyclodextrin complexes.

Quercetin is a bioactive flavonoid widely used as a health supplement. Being sparingly soluble and chemically unstable in aqueous intestinal fluids, quercetin is poorly absorbed orally. This study aimed to investigate the effects of three beta-cyclodextrins, namely, unsubstituted beta-cyclodextrin (beta-CD), hydroxypropyl-beta-cyclodextrin (HP-beta-CD), and sulfobutyl ether beta-cyclodextrin (SBE-beta-CD) on the chemical stability and water solubility of quercetin, and to elucidate the complexation mechanisms of these beta-CDs with quercetin. Quercetin-beta-CD complexes in solution were characterized by stability assessment, phase solubility measurements, and 1H-nuclear magnetic resonance (NMR) spectroscopy. Molecular modeling was used to help establish the mode of interaction of the beta-CDs with quercetin. Solubility enhancements of quercetin obtained with the three beta-CDs followed the rank order: SBE-beta-CD > HP-beta-CD > beta-CD. The stability of quercetin at alkaline pHs also showed substantial improvement. NMR spectroscopic analysis suggested that the B-ring, C-ring, and part of the A-ring of quercetin display favorable interaction with the hydrophobic cavity of the beta-CDs, which was confirmed by molecular dynamics (MD) simulations using a solvated model of the quercetin-beta-CD complex. An inclusion complex model has been established for explaining the observed augmentation of solubility and stability of quercetin in water by beta-CDs.

Chemical Phenomena↗
PubMed2005

Difference in absorption of the two structurally similar flavonoid glycosides, hyperoside and isoquercitrin, in rats.

The present study was to investigate oral absorption of the two similar flavonoid glycosides, isoquercitrin (IQ, quercetin-3-O-glucoside) and hyperoside (HP, quercetin-3-O-galactoside) in rats. Two groups of male SD rats received an oral dose of either IQ (4.5 mg/kg) or HP (6.0 mg/kg). Blood samples were collected via jugular vein at time intervals after drug administration and the plasma concentrations of the studied compounds were analyzed by HPLC. The stability of IQ and HP in the GI tract was also measured by incubation with various GI contents from rats. The results showed that unchanged IQ was barely detectable whereas the glucuronidated quercetin (the aglycone of IQ) was found to be the major form in plasma after oral administration of IQ. In contrast, HP could not be detected in plasma neither as unchanged form nor its aglycone or conjugated aglycone form. Additional in vitro stability studies demonstrated that HP is more stable than IQ in the GI tract. This suggests that IQ could be hydrolyzed easier than HP to its aglycone in GI tract before being absorbed. In conclusion, IQ, as a flavonoid glucoside, could be rapidly absorbed and transformed into glucuronidated quercetin and such absorption might be related to the hydrolysis of the type of sugar moieties attached to its aglycone molecule.

Animals↗
PubMed2005

Comparison of the pharmacokinetics of hawthorn phenolics in extract versus individual pure compound.

The pharmacokinetics of an active herbal substance may be different when administered in an extract form as compared to that when administered as a pure compound. This study investigated the pharmacokinetics of 4 active compounds of hawthorn fruits--namely, (-)-epicatechin, chlorogenic acid, hyperoside, and isoquercitrin--following administration of an extract formulation (as hawthorn phenolic extract, which contained the active compounds) or equivalent doses of individual pure compound in male Sprague-Dawley rats (n = 5 per group). The hawthorn phenolic extract or pure compounds were administered both orally and intravenously. Following administration, multiple plasma samples were obtained, and the plasma concentrations were determined by high-performance liquid chromatography. After the intravenous injection of hawthorn phenolic extract, higher plasma drug concentration, larger area under the plasma concentration-time curve from 0 to infinity, longer terminal elimination half-life, smaller apparent volume of distribution, lower total body clearance, and higher urinary excretion of each compound were obtained when compared to that after the pure compound. Following the oral administration of either hawthorn phenolic extract or pure compound, only epicatechin was absorbed, and their pharmacokinetics were generally not significantly different between these 2 formulations. The differences in the pharmacokinetics of the 2 formulations following intravenous but not oral administration may be attributable to the existence of other co-occurring components in the hawthorn phonolic extract (which may be present in the body after intravenous but not oral administration). The results showed that an herbal extract formulation, when administered intravenously, could potentially alter the pharmacokinetics of its active ingredients.

Administration, Oral↗
PubMed2005

Danshen: an overview of its chemistry, pharmacology, pharmacokinetics, and clinical use.

Danshen, the dried root of Salvia miltiorrhiza, has been widely used in China and, to a lesser extent, in Japan, the United States, and other European countries for the treatment of cardiovascular and cerebrovascular diseases. In China, the specific clinical use is angina pectoris, hyperlipidemia, and acute ischemic stroke. The current review covers its traditional uses, chemical constituents, pharmacological activities, pharmacokinetics, clinical applications, and potential herb-drug interactions based on information obtained in both the English and Chinese literature. Although numerous clinical trials have demonstrated that certain Danshen products in China are effective and safe for the treatment of cardiovascular diseases, most of these lack sufficient quality. Therefore, large randomized clinical trials and further scientific research to determine its mechanism of actions will be necessary to ensure the safety, effectiveness, and better understanding of its action.

Abietanes↗
PubMed2004

Evaluation of the first-pass glucuronidation of selected flavones in gut by Caco-2 monolayer model.

PURPOSE: Four flavones, namely Apigenin, Baicalein, Chrysin and Luteolin, were selected for study and comparison of their absorption and metabolism in gut using the in vitro Caco-2 monolayer model. METHODS: Transport of the four flavones in the Caco-2 monolayer model was studied in both Apical-to-Basolateral and Basolateral-to-Apical directions. RESULTS: All of the selected flavones were able to pass through the Caco-2 cell monolayer with no significant efflux. The permeability coefficients of the four compounds were all greater than 10(-6) cm/sec and those of Apigenin and Baicalein were even greater than 10(-5) cm/sec. Glucuronides of the tested flavones were all formed in the Caco-2 cell monolayer model and a structure-activity relationship has been proposed for this glucuronidation. In addition, Apical-to-Basolateral transport studies were performed in Caco-2 models pre-treated with Chrysin, an UGT inducer. Quantities of the corresponding glucuronides formed were all significantly higher in Chrysin-treated groups than the controls. CONCLUSIONS: It demonstrated that all selected flavones were substrates of the UGT isoforms that are inducible by Chrysin.

Biological Transport↗
PubMed2004

Investigation of intestinal absorption and disposition of green tea catechins by Caco-2 monolayer model.

The current study was designed to investigate the absorption mechanism and identify the possible disposition pathways of green tea catechins (GTC), including epicatechin (EC), epigallocatechin (EGC), epicatechin gallate (ECG) and epigallocatechin gallate (EGCG), during their absorption across small intestine by Caco-2 monolayer model. The transport of each GTC from both apical to basolateral and basolateral to apical directions was measured in the absence and the presence of MK571, an MRP inhibitor. HPLC and LC/MS were employed to identify the possible metabolites of the four GTC formed during their bidirectional transport processes. The results indicated that the four GTC showed limited transepithelial absorption with relatively small P(app) values. However, significant efflux mediated by MRP was observed during the secretion of GTC, especially the non-gallated catechins. Methylation and sulfation were the main biotransformation pathways of GTC during their secretion transport and the efflux of the related metabolites seem to be mediated by MRP.

Biological Transport↗
PubMed2004

High-performance liquid chromatographic method for simultaneous determination of baicalein and baicalein 7-glucuronide in rat plasma.

A simple HPLC method with ultraviolet detection was developed for the simultaneous determination of baicalein and its major metabolite, baicalein 7-glucuronide (baicalin) in rat plasma. Following solid phase extraction with HLB cartridge, the analytes were separated using a gradient mobile phase consisting of methanol-acetonitrile-phosphate buffer. The flow-rate was set at 1ml/min and the eluent was detected at 320nm. The method is linear over the studied range of 1-10 and 0.05-1microg/ml for baicalein and baicalin, respectively. The intra-day and inter-day variations of the analysis were less than 6.38%, with relative error ranging from -3.6 to 6%. The limit of quantification in plasma was 0.05microg/ml for both baicalein and baicalin. The developed method proves to be an improved and more reliable method because of its capability for determining baicalein and baicalin simultaneously in a single chromatographic run.

Animals↗