Yuhui Wei

Ethosomes, binary ethosomes and transfersomes of terbinafine hydrochloride: A comparative study

The aim of this study was to compare the skin permeation of ethosomes, binary ethosomes and transfersomes of Terbinafine Hydrochloride (TH) under non-occlusive conditions. These lipid vesicles were prepared and characterized for shape, size, zeta-potential and entrapment efficiency. Franz diffusion cells and confocal laser scanning microscopy (CLSM) were used for the percutaneous absorption studies. The quantity of drug in the skin from ethosomes, binary ethosomes (the weight ratio of ethanol to propylene glycol 7:3, ethanol-PG = 7:3, w/w), and transfersomes was 1.26, 1.51 (p <0.05), 1.56 (p <0.01) times higher than that of TH from traditional liposomes (control). The skin deposition of the applied dose (DD%) of TH from ethosomes, binary ethosomes, and transfersomes was 3.34 (p < 0.05), 9.88 (p < 0.01), 2.52 times higher than that of TH from control. The results of CLSM experiments showed that penetration depth and fluorescence intensity of Rhodamine B from binary ethosomes was much greater than that from ethosomes and transfersomes. These results indicated the binary ethosomes (ethanol-PG = 7:3, w/w) most effectively permitted drug penetration through skin; transfersomes made drug easiest to accumulate in the skin. Ethosomes improved drug delivery with greater improvement in skin permeation than improvement in skin deposition.

Effects of Pluronic F68 and Labrasol on the intestinal absorption and pharmacokinetics of rifampicin in rats

The aim of this study was to investigate the effects of Pluronic F68 and Labrasol on the intestinal absorption and pharmacokinetics of rifampicin. Intestinal permeability of rifampicin with or without excipients was evaluated by an in situ single-pass perfusion method. A highperformance liquid chromatographic method was applied to study the pharmacokinetics of rifampicin with or without excipients. Labrasol or Pluronic F68 (0.1% and 0.05%, v/v), co-perfused with rifampicin (60 μg/mL), significantly increased in situ permeability. Similarly, verapamil (a typical P-gp inhibitor) also increased in situ permeability, but to a lesser extent. In vivo, the oral administration of rifampicin with or without Pluronic F68, Labrasol or verapamil resulted in statistically significant effect on t1/2 (4.83 to 7.75, 6.42 and 7.46 h) and total body clearance (0.46 to 0.26, 0.28, 0.24 L/h/kg). In addition, Pluronic F68, Labrasol and verapamil produced minor changes in AUC0−t, which improved 1.55-, 1.54-, and 1.73-fold in comparison to control group, respectively. These results showed that Labrasol and Pluronic F68 might inhibit the function of P-gp in the intestine, thereby increasing intestinal absorption and changing the pharmacokinetic parameters of rifampicin. Therefore, excipient selection is an important factor to consider in rational formulation design.

Synergistic penetration of ethosomes and lipophilic prodrug on the transdermal delivery of acyclovir

The aim of this study was to investigate the lipophilic prodrug as a means of promoting acyclovir (ACV) that exhibited biphasic insolubility into the ethosomes for optimum skin delivery. Acyclovir Palmitate (ACV-C16) was synthesized as the lipophilic prodrug of ACV. The ethosomal system and the liposomal system bearing ACV or ACV-C16 were prepared, respectively. The systems were characterized for shape, zeta potential value, particle size, and entrapment efficiency. Franz diffusion cells and confocal laser scanning microscopy were used for the percutaneous absorption studies. The results showed that the entrapment efficiency of ACV-C16 ethosomes (87.75%) were much higher than that of ACV ethosomes (39.13%). The quantity of drug in the skin from ACV-C16 ethosomes at the end of the 24 h transdermal experiment (622.89 μg/cm2) was 5.30 and 3.43 times higher than that from ACV-C16 hydroalcoholic solution and ACV ethosomes, respectively. This study indicated that the binary combination of the lipophilic prodrug ACV-C16 and the ethosomes synergistically enhanced ACV absorption into the skin.

Development of a dynamic multiple reaction monitoring method for determination of digoxin and six active components of Ginkgo biloba leaf extract in rat plasma

A new liquid chromatography-tandem mass spectrometry (LC-MS/MS) method by using dynamic multiple reaction monitoring (DMRM) has been developed and validated for the simultaneous determination of digoxin (DGX) and six main components of Ginkgo biloba leaf extract (GBE) in rat plasma. Comparing with the conventional multiple reaction monitoring (MRM), DMRM dramatically decreases the number of concurrent MRM transitions, and significantly extended the dwell time, which provided much higher sensitivity and reproducibility than MRM when complex multi-component samples were quantified. The plasma samples were protein precipitated with methanol, the detection was accomplished with electro-spray ionization (ESI) as the ion source operating in the negative ionization mode, with methanol and water as mobile phase, and with an Agilent Zorbax eclipse plus C18 column (4.6 × 100 mm, 3.5 μm) as the analytical column. The total run time was 12.0 min. The validation of the method was implemented including specificity, linearity, accuracy, precision, recovery, matrix effect and stability. This method was successfully applied to the herb-drug pharmacokinetic interaction study of DGX combined with GBE after oral administration to rats. The result indicated that co-administration of GBE and DGX significantly influenced the pharmacokinetics of DGX when compared to that of single DGX-treated rats.

Mucoadhesive microparticulates based on polysaccharide for target dual drug delivery of 5-aminosalicylic acid and curcumin to inflamed colon

In this work, thiolated chitosan/alginate composite microparticulates (CMPs) coated by Eudragit S-100 were developed for colon-specific delivery of 5-aminosalicylic acid (5-ASA) and curcumin (CUR), and the use of it as a multi drug delivery system for the treatment of colitis. The physicochemical properties of the CMPs were evaluated. In vitro release was performed in gradually pH-changing medium simulating the conditions of different parts of GIT, and the results showed that the Eudragit S-100 coating has a pH-sensitive release property, which can avoid drug being released at a pH lower than 7. An everted sac method was used to evaluate the mucoadhesion of CMPs. Ex vivo mucoadhesive tests showed CMPs have excellent mucosa adhesion for the colonic mucosa of rats. In vivo treatment effect of enteric microparticulates systems was evaluated in colitis rats. The results showed superior therapeutic efficiency of this drug delivery system for the colitis rats induced by TNBS. Therefore, the enteric microparticulates systems combined the properties of pH dependent delivery, mucoadhesive, and control release, and could be an available tool for the treatment of human inflammatory bowel disease.

Effect of Yin-Zhi-Huang on up-regulation of Oatp2, Ntcp, and Mrp2 proteins in estrogen-induced rat cholestasis.

Abstract Context: Yin–Zhi–Huang (YZH), a prescription of traditional Chinese medicine, is widely used to treat neonatal jaundice or cholestasis. Objective: This study investigates the regulatory effect of YZH on the localization and expression of organic anion transporting polypeptides 2 (Oatp2), Na+-taurocholate co-transporting polypeptide (Ntcp), multidrug-resistance-associated protein 2 (Mrp2), and bile salt export pump (Bsep) in estrogen-induced cholestasis rats. Material and methods: Cholestasis model rats were induced via subcutaneous injection of estradiol benzoate (EB, 5 mg/kg/d) for 5 d. Other EB-induced rats were treated with saline (2 ml) or YZH (1.5 g/kg, two times a day) for 7, 14, and 21 d. The biochemical and pathologic examinations were performed. Moreover, the localization and expression of Oatp2, Ntcp, Mrp2, and Bsep were determined by immunohistochemisty and Western blotting, respectively. Results: YZH treatment could significantly decrease the serum total bile acids (TBA) (4.9 ± 0.6–2.8 ± 0.8) and direct bilirubin (DBIL) (2.6 ± 0.7–1.0 ± 0.1) levels, improve the histological disorganization, and, respectively, increase the expression of Oatp2 and Ntcp by 46% and 28% compared with saline-treated (p < 0.05) rats at 14 d. The expression of Mrp2 increased by 45% was observed in YZH treated compared with saline-treated (p < 0.05) rats at 7 d. However, there was a little change in the expression of Bsep (p > 0.05) after YZH treatment for 7, 14, and 21 d. Discussion and conclusion: In conclusion, the therapeutic effect of YZH to cholestasis could be attributed to the regulation of Oatp2, Ntcp, Mrp2, and Bsep.

Quantitative structure-activity relationship analysis of a series of human renal organic anion transporter inhibitors.

Organic anion transporters (OATs) have been proved to play important roles in the membrane transport of numerous potentially toxic xenobiotics, drugs, and endogenous metabolites. In general, OATs substrates can compete with one another for the transporter to mutually decrease renal secretion and thus delay the clearance and prolong the duration of action of each compound. Such interactions have the potential to bring about adverse outcomes for clinical cases. Therefore, it is very important to assess the molecular bioactivity to inhibit OATs during the development of new drugs and co‐administration. In this work, the relationships between 45 chemicals and their corresponding hOAT1 and hOAT3 inhibitory activities were analyzed. The quantitative structure–activity relationship (QSAR) model was developed by genetic algorithm and multiple linear regression method. The predictive power of the proposed model was strictly evaluated, and the applicability domain was also defined. The proposed models were robust and satisfactory and could provide a feasible and effective tool for hOAT1 or hOAT3 inhibitor screening.

Development of a LC-MS/MS method for simultaneous determination of metoprolol and its metabolites, α-hydroxymetoprolol and O-desmethylmetoprolol, in rat plasma: application to the herb–drug interaction study of metoprolol and breviscapine

A simple, specific and sensitive LC-MS/MS method was developed and validated for the simultaneous determination of metoprolol (MET), α-hydroxymetoprolol (HMT) and O-desmethylmetoprolol (DMT) in rat plasma. The plasma samples were prepared by protein precipitation, then the separation of the analytes was performed on an Agilent HC-C18 column (4.6 × 250 mm, 5 µm) at a flow rate of 1.0 mL/min, and post-column splitting (1:4) was used to give optimal interface flow rates (0.2 mL/min) for MS detection; the total run time was 8.5 min. Mass spectrometric detection was achieved using a triple-quadrupole mass spectrometer equipped with an electrospray source interface in positive ionization mode. The method was fully validated in terms of selectivity, linearity, accuracy, precision, stability, matrix effect and recovery over a concentration range of 3.42-7000 ng/mL for MET, 2.05-4200 ng/mL for HMT and 1.95-4000 ng/mL for DMT. The analytical method was successfully applied to herb-drug interaction study of MET and breviscapine after administration of breviscapine (12.5 mg/kg) and MET (40 mg/kg). The results suggested that breviscapine have negligible effect on pharmacokinetics of MET in rats; the information may be beneficial for the application of breviscapine in combination with MET in clinical therapy.

Non-covalent modification of thrombolytic agent nattokinase: simultaneous improvement of fibrinolysis activity and enzymatic stability

Cardiovascular disease (CVD) has become the leading cause of death globally. Nattokinase (NK), as a novel thrombolytic agent, has gained more and more attention. However, NK is susceptible to chemical oxidation, and subsequent inactivation denaturation. Modification of an enzyme to improve its stability usually brings about falling enzymatic activity. In this study, folic acid modified chitosan (CS-FA) was synthesized, and a series of NK/CS-FA complexes with different mass ratios were prepared. In vitro thrombolysis experiments indicated that NK/CS-FA showed obvious advantages in its fibrinolysis activity and stability. With the NK : CS-FA mass ratio of 100 : 1 (molar ratio of NK : chitosan pyranose ring = 3 : 5), NK/CS-FA 100 : 1 exhibited the best fibrinolysis activity and the thrombi dissolved completely within 17 hours at a constant rate, while the un-modified NK dissolved only 35 wt% of the thrombus in the same duration. NK/CS-FA 100 : 1 retained more than 53% enzymatic activity at 80 °C or pH 2, as a comparison, only 17% enzymatic activity was left for un-modified NK under the same conditions.

In Silico Study Combining Docking and QSAR Methods on a Series of Matrix Metalloproteinase 13 Inhibitors

Matrix metalloproteinase 13 (MMP‐13) plays an important role in the degradation of articular cartilage and has been considered as an attractive target for the treatment of osteoarthritis; hence, the development of efficient inhibitors of MMP‐13 has become a hot study field. Taking a series of carboxylic acid‐based MMP‐13 inhibitors as research object, this work utilized an extended QSAR method to analyze the structure–activity relationships. We focused on two important topics in QSAR: bioactive conformation and descriptors. Firstly, molecular docking was carried out to dock all molecules into the MMP‐13 active site in order to obtain the bioactive conformation. Secondly, based on the docked complex, descriptors characterizing receptor–ligand interactions and the ligand structure were calculated. Thirdly, a genetic algorithm (GA) and multiple linear regression (MLR) were employed to select important descriptors related to inhibitory activities, simultaneously, to build the predictive model. The built model gave satisfactory results with highly accurate fitting and strong external predictive abilities for chemicals not used in model development. Furthermore, the selected descriptors were explored to elucidate important factors influencing the inhibition activities. This study demonstrates that the selection strategy of the docking‐guided bioactive conformation is rational and useful in predicting MMP‐13 inhibitor activities, and receptor–ligand complex descriptors have an advantage over directly reflecting receptor–ligand interactions.