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OBJECTIVE：To analyze the mass spectrometry fragmentation regularity of bicyclol ，bifendate and schisandrin C ， and to identify the impurities of bicyclol raw material. METHODS ：UHPLC-ESI-Q-TOF-MS method was adopted. Using electrospray ionization source ，in positive ion mode ，the excimer ion and characteristic fragments of bicyclol ，bifendate and schisandrin C were analyzed by means of TOF-MS. According to the mass change of fragments ，the possible fragmentation pathways were speculated ，and the fragmentation regularity were analyzed and summarized. Bicyclol raw material sample was first separated by liquid chromatography to find the impurity peaks in it ，and then the impurity peaks were analyzed by mass spectrometer；the impurity identification was conducted by combining with the fragmentation regularity. RESULTS ：The 3 compounds all produced [M+H] + excimer ion in the positive ion mode. After collision-induced dissociation ，the C-O bond ，the simple rupture of the C-C bond and the ring-opening cleavage of the oxygen ring occurred ；with the loss of neutral fragments ， mainly CH 2O，supplemented by CO 2，CO and CHO ，the dissociation was concentrated in the middle and high quality regions. C-C and C-O bonds of 3 compounds were simply broken only in the branched chain structure and/or oxygen ring structure ，but the structure of the biphenyl parent nucleus remained unchanged. Among them ，the bicyclol contained a benzyl alcohol structure ，so under acidic mobile phase conditions ，it would exist stably in the form of [M+H －H2O]+. Because schisandrin C contained 8-membered ring structure，ring opening first occurred under collision voltage ，and then neutral fragment loss occurred. The secondary mass spectra of impurity in bicyclol raw material were consistent with the mass spectra fragmentation of secondary fragments of bifendate. CONCLUSIONS：The study summarized mass spectrometry fragmentation regularity of 3 schisandrin derivatives. The impurity in bicyclol raw material may be bifendate.
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Objective To research the influence of Alismatis combined with bifendate on cytochrome P 450 in rat liver microsomes. Methods Twenty four healthy male SD rats were randomly divided into four groups:the experimental groups were given Alismatis at 140 mg·kg-1 , bifendateat 2.18 mg·kg-1 , and Alismatis plus bifendate at 140 mg+2.18 mg·kg-1 ,while the blank control group was given 0. 9% sodium chloride at 5 Ml · kg-1 . The liver microsomes were prepared upon differential centrifugation 7 days after administration.The microsomal protein concentration, cytochrome P450 content, Cytb5 content, NADPH cytochrome C reductase activity and amino pyrine N removal of methyl enzyme activity, erythromycin demethylase activity were determined by UV respectively. Results Compared with the normal control group, the combination use of Alismatis and bifendate redued the microsome content and cytochrome P450 content, while it increased the NADPH cytodrome C activity. The concentrations of cytochrome P450 were both increased by Alismatis and bifendate. Conclusion In contrast, combination ofAlismatis and bifendate reduces cytochrome P450 content which has a negative effect on phase I drug metabolism.Moreover, the combination of Alismatis and bifendate induced NADPH- cytochrome C reductase, accelerated the reduction of cytochrome P450 and inhibited cytochrome P450 isoform CYP2E1 activity.
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Objective To research the influence of Alismatis combined with bifendate on cytochrome P 450 in rat liver microsomes. Methods Twenty four healthy male SD rats were randomly divided into four groups:the experimental groups were given Alismatis at 140 mg·kg-1 , bifendateat 2.18 mg·kg-1 , and Alismatis plus bifendate at 140 mg+2.18 mg·kg-1 ,while the blank control group was given 0. 9% sodium chloride at 5 Ml · kg-1 . The liver microsomes were prepared upon differential centrifugation 7 days after administration.The microsomal protein concentration, cytochrome P450 content, Cytb5 content, NADPH cytochrome C reductase activity and amino pyrine N removal of methyl enzyme activity, erythromycin demethylase activity were determined by UV respectively. Results Compared with the normal control group, the combination use of Alismatis and bifendate redued the microsome content and cytochrome P450 content, while it increased the NADPH cytodrome C activity. The concentrations of cytochrome P450 were both increased by Alismatis and bifendate. Conclusion In contrast, combination ofAlismatis and bifendate reduces cytochrome P450 content which has a negative effect on phase I drug metabolism.Moreover, the combination of Alismatis and bifendate induced NADPH- cytochrome C reductase, accelerated the reduction of cytochrome P450 and inhibited cytochrome P450 isoform CYP2E1 activity.
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Objective:To investigate the in vitro release behavior and stability of diphenyl diester suspension. Methods:The dis-solution of biphenyl diester dry suspension was detected by HPLC, and the effects of different stirring speed (50, 75, 100 r·min-1 ) and different dissolution media (pH 6. 8 phosphate buffer, 0. 05 mol·L-1 hydrochloric acid solution,water,pH 4. 5 acetate buffer) on dissolution were investigated. The influencing factors testing ( high temperature, high humidity and strong light exposure) , accelerated stability testing[the temperature of (37 ± 5) ℃ and the relative humidity of 76％ ± 5％] and long-term stability testing[(25 ± 3) ℃and the relative humidity of 60％ ± 5 ％] of biphenyl diester dry suspension were carried out. Results:The dissolution behavior of bi-phenyl diester suspension in pH 6. 8 phosphate buffer (50 r·min-1 ) was faster and smoother. The results of influencing factors testing showed that biphenyl diester dry suspension should not be stored under the conditions of high temperature and high humidity. After the samples were stored under the conditions of accelerated testing and long-term stability testing for 6 months, the indicators did not change significantly. Conclusion:The in vitro release of prepared biphenyl diester dry suspension meets the requirements with promis-ing stability.
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Bifendate, a synthetic anti-hepatitis drug, exhibits polycrystalline mode phenomena with 2 polymorphs reported (forms A and B). Single crystals of the known crystalline form B and 3 new crystallosolvates involving bifendate solvated with tetrahydrofuran (C), dioxane (D), and pyridine (E) in a stoichiometric ratio of 1:1 were obtained and characterized by X-ray crystallography, thermal analysis, and Fourier transform infrared (FT-IR) spectroscopy. The differences in molecular conformation, intermolecular interaction and crystal packing arrangement for the four polymorphs were determined and the basis for the polymorphisms was investigated. The rotation of single bonds resulted in different orientations for the biphenyl, methyl ester and methoxyl groups. All guest solvent molecules interacted with the host molecule via an interesting intercalative mode along the [1 0 0] direction in the channel formed by the host molecules through weak aromatic stacking interactions or non-classical hydrogen bonds, of which the volume and planarity played an important role in the intercalation of the host with the guest. The incorporation of solvent-augmented rotation of the C-C bond of the biphenyl group had a striking effect on the host molecular conformation and contributed to the formation of bifendate polymorphs. Moreover, the simulated powder X-ray diffraction (PXRD) patterns for each form were calculated on the basis of the single-crystal data and proved to be unique. The single-crystal structures of the four crystalline forms are reported in this paper.
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OBJECTIVE:To study the tissue distribution and liver-targeting activity of bifendate solid lipid nanoparticles (DDB-SLN) in mice.METHODS:A total of 60 mice were injected with DDB-SLN or DDB solution (DDBS) with DDB dosage at 20 mg?kg-1.Sampling was scheduled at 0.083,0.25,1,3 and 5 hours,and HPLC was employed to determine and compute the concentrations of DDB in plasma,heart,liver,spleen,lung,kidney and brain as well as the Drug Targeting Index (DTI) and the Drug Selecting Index (DSI) of DDB-SLN on DDBS.RESUTLS:The DDB concentrations in liver were the highest for both groups.At 0.25,1,3 and 5 h,the DDB concentrations in liver in DDB-SLN group were 1.15,3.04,2.72 and 3.62 times those in DDBS group.The DTI of DDB-SLN were 1.151,3.038,2.720 and 3.622,respectively and the DSI were 3.269,7.891,5.948 and 7.759,respectively.CONCLUSION:As compared with DDBS,DDB-SLN is a more potent liver-targeting drug.