The therapeutic potential of saquinavir, a specific inhibitor of human immunodeficiency virus(HIV)-1 and HIV-2 protease enzymes, has been largely limited because of a low solubility and consequnt low bioavailability. ...The therapeutic potential of saquinavir, a specific inhibitor of human immunodeficiency virus(HIV)-1 and HIV-2 protease enzymes, has been largely limited because of a low solubility and consequnt low bioavailability. Thus, we aimed to design a supersaturated selfmicroemulsifying drug delivery system(S-SMEDDS) that can maintain a high concentration of saquinavir in gastro-intestinal fluid thorugh inhibiting the drug precipitation to enhance the lymphatic transport of saquinavir and to increase the bioavailability of saquinavir considerably. Solubilizing capacity of different oils, surfactants, and cosurfactants for saquinavir was evaluated to select optimal ingredients for preparation of SMEDDS.Through the construction of pseudo-ternary phase diagram, SMEDDS formulations were established. A polymer as a precipitation inhibitor was selected based on its viscosity and drug precipitation inhibiting capacity. The S-SMEDDS and SMEDDS designed were administered at an equal dose to rats. At predetermined time points, levels of saquinavir in lymph collected from the rats were assessed. SMEDDS prepared presented a proper selfmicroemulsification efficiency and dispersion stability. The S-SMEDDS fabricated using the SMEDDS and hydroxypropyl methyl cellulose 2910 as a precipitation inhibitor exhibited a signficantly enhanced solubilizing capacity for saquinavir. The drug concentration in a simulated intestinal fluid evaluated with the S-SMEDDS was also maintained at higher levels for prolonged time than that examined with the SMEDDS. The S-SMEDDS showed a considerably enhanced lymphatic absoprtion of saquinavir in rats compared to the SMEDDS.Therefore, the S-SMEDDS would be usefully exploited to enhance the lymphatic absorption of hydrophobic drugs that need to be targeted to the lymphatic system.展开更多
An improved synthetic method of saquinavir, an HIV protease inhibitor, is described. In comparison with the methods in the reported works, the improved procedures had several advantages, such as less expensive agents,...An improved synthetic method of saquinavir, an HIV protease inhibitor, is described. In comparison with the methods in the reported works, the improved procedures had several advantages, such as less expensive agents, shorter reaction time, and a smaller amount of the solvent needed. To measure the optical purities of the products, the intermediates were determined by means of chiral HPLC. Some of the intermediates can also be used for the preparation of new protease inhibitors.展开更多
In the present study, a rapid and sensitive liquid chromatography-tandem mass spectrometric method for the determination of saquinavir in mice plasma and brain was developed, validated, and applied to a preliminary sc...In the present study, a rapid and sensitive liquid chromatography-tandem mass spectrometric method for the determination of saquinavir in mice plasma and brain was developed, validated, and applied to a preliminary screening study evaluating the effect of bioflavonoids on the brain distribution of saquinavir in mice. Saquinavir and the internal standard（ritonavir） were isolated from plasma and homogenized brain tissue matrices using a liquid-liquid extraction procedure, and the chromatographic separation was accomplished by using a reversed phase C18 column（150 mm×2.1 mm, 5.0 μm）. The analyte was detected by a triple-quadrupole tandem mass spectrometer via electrospray ionization, and multiple reaction monitoring was employed to select both saquinavir and ritonavir in the positive ion mode. A linear dynamic range of 0.1–10 ng/m L for plasma samples was established and the lower limit of quantification was 0.1 ng/m L. The intra- and inter-day precision were 7.5%–12.1%, and the accuracies ranged from 90.5% to 107.2% for plasma. A linear dynamic range of 0.1–10 ng/g for brain samples was established and the lower limit of quantification was 0.1 ng/g. The intra- and inter-day precision were 7.3%–11.9%, and the accuracies ranged from 90.8% to 107.4% for brain tissue samples. This method was successfully applied a preliminary screen of 19 bioflavonoids on the brain distribution of saquinavir in mice, and biochanin A shows the strongest effect.展开更多
目的研究酮康唑对沙奎那韦的体外代谢和药物代谢动力学的影响。方法沙奎那韦分别与氟伏沙明、奎尼丁、胺碘酮、酮康唑在人肝微粒体中共同孵育,观察后者对沙奎那韦体外代谢的影响。另将沙奎那韦与酮康唑同时对Sprague-Dawley大鼠颈动脉...目的研究酮康唑对沙奎那韦的体外代谢和药物代谢动力学的影响。方法沙奎那韦分别与氟伏沙明、奎尼丁、胺碘酮、酮康唑在人肝微粒体中共同孵育,观察后者对沙奎那韦体外代谢的影响。另将沙奎那韦与酮康唑同时对Sprague-Dawley大鼠颈动脉注射给药,观察后者对沙奎那韦药代动力学的影响。结果酮康唑对沙奎那韦体外代谢有明显的抑制作用,而氟伏沙明、奎尼丁、胺碘酮对沙奎那韦体外代谢没有明显的抑制作用。酮康唑能改变沙奎那韦的AUC值(由169.68±20.38增加至252.39±50.65mg.m in-1.L-1),CL值(由29.47±7.00下降至19.81±3.05 m l.m in-1.kg-1),T1/2(由1.23±0.30 m in下降至0.89±0.35m in)。结论酮康唑能显著抑制沙奎那韦的体外代谢,同时酮康唑对沙奎那韦的药代动力学参数也有一定影响。展开更多
基金the National Research Foundation of Korea(NRF)grant funded by the Korea government(MSIP)(no.2015R1A5A1008958)supported by the Industry Technology Development Program(10077593)funded by the Ministry of Trade,Industry&Energy(MOTIE,Korea)。
文摘The therapeutic potential of saquinavir, a specific inhibitor of human immunodeficiency virus(HIV)-1 and HIV-2 protease enzymes, has been largely limited because of a low solubility and consequnt low bioavailability. Thus, we aimed to design a supersaturated selfmicroemulsifying drug delivery system(S-SMEDDS) that can maintain a high concentration of saquinavir in gastro-intestinal fluid thorugh inhibiting the drug precipitation to enhance the lymphatic transport of saquinavir and to increase the bioavailability of saquinavir considerably. Solubilizing capacity of different oils, surfactants, and cosurfactants for saquinavir was evaluated to select optimal ingredients for preparation of SMEDDS.Through the construction of pseudo-ternary phase diagram, SMEDDS formulations were established. A polymer as a precipitation inhibitor was selected based on its viscosity and drug precipitation inhibiting capacity. The S-SMEDDS and SMEDDS designed were administered at an equal dose to rats. At predetermined time points, levels of saquinavir in lymph collected from the rats were assessed. SMEDDS prepared presented a proper selfmicroemulsification efficiency and dispersion stability. The S-SMEDDS fabricated using the SMEDDS and hydroxypropyl methyl cellulose 2910 as a precipitation inhibitor exhibited a signficantly enhanced solubilizing capacity for saquinavir. The drug concentration in a simulated intestinal fluid evaluated with the S-SMEDDS was also maintained at higher levels for prolonged time than that examined with the SMEDDS. The S-SMEDDS showed a considerably enhanced lymphatic absoprtion of saquinavir in rats compared to the SMEDDS.Therefore, the S-SMEDDS would be usefully exploited to enhance the lymphatic absorption of hydrophobic drugs that need to be targeted to the lymphatic system.
文摘An improved synthetic method of saquinavir, an HIV protease inhibitor, is described. In comparison with the methods in the reported works, the improved procedures had several advantages, such as less expensive agents, shorter reaction time, and a smaller amount of the solvent needed. To measure the optical purities of the products, the intermediates were determined by means of chiral HPLC. Some of the intermediates can also be used for the preparation of new protease inhibitors.
基金National Natural Science Foundation of China(NSFC,Grant No.81102877)
文摘In the present study, a rapid and sensitive liquid chromatography-tandem mass spectrometric method for the determination of saquinavir in mice plasma and brain was developed, validated, and applied to a preliminary screening study evaluating the effect of bioflavonoids on the brain distribution of saquinavir in mice. Saquinavir and the internal standard（ritonavir） were isolated from plasma and homogenized brain tissue matrices using a liquid-liquid extraction procedure, and the chromatographic separation was accomplished by using a reversed phase C18 column（150 mm×2.1 mm, 5.0 μm）. The analyte was detected by a triple-quadrupole tandem mass spectrometer via electrospray ionization, and multiple reaction monitoring was employed to select both saquinavir and ritonavir in the positive ion mode. A linear dynamic range of 0.1–10 ng/m L for plasma samples was established and the lower limit of quantification was 0.1 ng/m L. The intra- and inter-day precision were 7.5%–12.1%, and the accuracies ranged from 90.5% to 107.2% for plasma. A linear dynamic range of 0.1–10 ng/g for brain samples was established and the lower limit of quantification was 0.1 ng/g. The intra- and inter-day precision were 7.3%–11.9%, and the accuracies ranged from 90.8% to 107.4% for brain tissue samples. This method was successfully applied a preliminary screen of 19 bioflavonoids on the brain distribution of saquinavir in mice, and biochanin A shows the strongest effect.
文摘目的研究酮康唑对沙奎那韦的体外代谢和药物代谢动力学的影响。方法沙奎那韦分别与氟伏沙明、奎尼丁、胺碘酮、酮康唑在人肝微粒体中共同孵育,观察后者对沙奎那韦体外代谢的影响。另将沙奎那韦与酮康唑同时对Sprague-Dawley大鼠颈动脉注射给药,观察后者对沙奎那韦药代动力学的影响。结果酮康唑对沙奎那韦体外代谢有明显的抑制作用,而氟伏沙明、奎尼丁、胺碘酮对沙奎那韦体外代谢没有明显的抑制作用。酮康唑能改变沙奎那韦的AUC值(由169.68±20.38增加至252.39±50.65mg.m in-1.L-1),CL值(由29.47±7.00下降至19.81±3.05 m l.m in-1.kg-1),T1/2(由1.23±0.30 m in下降至0.89±0.35m in)。结论酮康唑能显著抑制沙奎那韦的体外代谢,同时酮康唑对沙奎那韦的药代动力学参数也有一定影响。
