血浆中辛伐他汀分析方法及药代动力学研究

采用ＧＣ／ＭＳ的ＳＩＭ定量模式,以洛伐他汀做内标,经乙酸乙酯萃取后,测定人体血中辛伐他汀的浓度。标准曲线在０．２７－５４μｇ／Ｌ之间呈良好的线性关系,ｒ〉０．９９９,高中低３个浓度点的日间日内ＲＳＤ小于５．２％,回收率可达９６％－１０３％〈并应用在１０例健康志愿者口服４０ｍｇ辛伐他汀的药代动力学的研究。     

辛伐他汀的波谱学数据和结构确证

对辛伐他汀的红外(IR)、紫外(UV)、质谱(MS)、氢-氢相关谱(^1H-^1HCOSY)、碳谱(^13C NMR,DEPT)、碳氢相关谱(HMQC)、碳氢远程相关谱(HMBC)予以解析并进行了报道,对所有的^1H NMR和^13C NMR谱信号进行了归属;讨论了红外特征吸收峰所对应的官能团的振动形式,并且对样品进行热差和热重分析,显示该样品为单一晶型,不含结晶水。     

用顶空气相色谱法测定西伐他汀中甲苯残留量

建立了用顶空ＧＣ法测定西伐他汀中甲苯残留量的方法,选用４０１有机担体作色谱柱,用５０ｇ／Ｌ十二烷基硫酸钠水溶液作溶剂。线性范围为０．５～４．０ｍｇ／Ｌ,ｒ＝０．９９８７;平均回收率为１０３．０６％。该法灵敏度高、简便、准确。甲苯的最低检测限为０．５ｍｇ／Ｌ。     

辛伐他汀的鉴定与分析

对辛伐他汀的^13C NMR及质谱解析进行了报道,并与其结构类似化合物的相应数据进行了比较。采用两种联动扫描方式确定了某些特征离子的子离子,并据此提出辛伐他汀的碎裂途径。在以ODZ柱和甲醇/水为淋洗液的条件下,HPLC可以完全分离辛伐他汀和洛伐他汀杂质,从而可以用此法对辛伐他汀进行质量C分析。     

HMG-CoA Reductase Inhibitor Regulates Endothelial Progenitor Function Through the Phosphatidylinositol 3′-Kinase/AKT Signal Transduction Pathway

HMG-CoA reductase inhibitor (statins) are known to have pleiotropic effects. We examined the effect and mechanism of simvastatin on peripheral endothelial progenitor cells (EPCs). Rats were divided into simvastatin group and the control group after cardiac infarction operation. Simvastatin treatment significantly increased the number of peripheral blood CD34+ CD133+ cells, and serum concentration of vascular endothelial growth factor (VEGF) and AKT was markedly increased in vivo. In cultured EPC, simvastatin increased the concentrations of VEGF, AKT and eNOS. Western blots analysis showed that simvastatin increased the phosphorylation of eNOS and FKHRL1, which can be blocked by the PI3K/AKT pathway blocker LY294002 . Our study demonstrated that simvastatin increases the mobilization of EPCs after cardiac infarction. In in vitro study, simvastatin increases the phosphorylation of eNOS and of FKHRL1 through the PI3K/AKT signaling pathway.     

The use of isothermal titration calorimetry to assess the solubility enhancement of simvastatin by a range of surfactants

Surfactants are commonly used to increase the solubility of poorly water soluble drugs but the interactions between drug and surfactant can be complex and quantitative relationships can be hard to derive. One approach is to quantify the thermodynamics of interaction and relate these parameters to known solubility or dissolution rate enhancement data. Isothermal titration calorimetry (ITC) was used to measure the enthalpy and free energy of transfer of a model drug (simvastatin) to a number of surfactant (SDS, HTAB, SDCH and Brij 35) micelles. These data were then compared with the solubility enhancements determined for each surfactant using HPLC assays. As expected, there was correlation between the free energy of transfer for the drug to each surfactant and the solubility enhancement of that surfactant. Although the data set is limited, the results suggest that ITC screening of a range of surfactants against a poorly water soluble drug may allow the selection of the best potential solubilising surfactants.     

Retention modelling in liquid chromatographic separation of simvastatin and six impurities using a microemulsion as eluent

A novel and unique approach was used for retention modelling in the separation of simvastatin and six impurities by liquid chromatographic using a microemulsion as mobile phase. A microemulsion is a modification of a micellar system where a lipophilic organic solvent is dissolved in the micelles; for that reason, microemulsions are usually treated as solvent-modified micellar solutions. When microemulsions are used as eluents in HPLC separations, solutes partition between the charged oil droplets and the aqueous buffer phase. The complexity of the composition of the microemulsion permits extensive manipulations to be made during method development in order to achieve acceptable resolution of such a complex mixture of substances. In order to avoid a laborious "trial and error" procedure, a 2(3) full factorial design was applied for choosing an optimal microemulsion composition to obtain good separation in a reasonable run time. Organic solvent, sodium dodecyl sulphate, and n-butanol content were varied within defined experimental domain. Optimal conditions for the separation of simvastatin and its six impurities were obtained using an X Terra 50 x 4.6 mm, 3.5 microm particle size column at 30 degrees C. The mobile phase consisted of 0.9% w/w of diisopropyl ether, 2.2% w/w of sodium dodecylsulphate (SDS), 7.0% w/w of co-surfactant such as n-butanol, and 89.9% w/w of aqueous 25 mM disodium phosphate pH 7.0.     

The rapid detection and identification of the impurities of simvastatin using high resolution sub 2 microm particle LC coupled to hybrid quadrupole time of flight MS operating with alternating high-low collision energy

The profiling and identification of impurities in raw pharmaceuticals or finished drug product is an essential part of the pharmaceutical manufacturing process. Critical to this process is the ability to confirm known, expected impurities and identify new impurities. LC coupled to electrospray MS is a powerful tool that has been employed for the identification of impurities, natural products, drug metabolites, and proteins. In this study, we show how sub 2 microm porous particle LC has been coupled to hybrid quadrupole orthogonal TOF mass spectrometer to profile and identify the impurities of the common cholesterol lowering drug simvastatin. The hybrid quadrupole TOF mass spectrometer was operated by alternating the collision cell energies to allow for the rapid, facile conformation of the identity of impurities. Using this process it was possible to identify all of the common impurities of simvastatin in a single 10 min run. During the analysis a new impurity of simvastatin was detected and identified as the saturated ring form of simvastatin.     

Simultaneous determination of simvastatin and simvastatin acid in human plasma by LC-MS/MS without polarity switch: application to a bioequivalence study

A simple, specific and sensitive LC-MS/MS assay for simultaneous determination of simvastatin (SV) and its active beta-hydroxy acid metabolite, simvastatin acid (SVA) in human plasma was developed using a statin analog as internal standard (IS). The method was validated over a dynamic linear range of 0.20-100.00 ng/mL for SV and 0.10-50.00 ng/mL for SVA with correlation coefficient r > or = 0.9987 and 0.9989, respectively. The analytes and IS were extracted from 500 microL aliquots of human plasma via liquid-liquid extraction using methyl tert-butyl ether and separated through an Aquasil C18 column (100 mm x 2.1 mm, 5 microm). Detection of analytes and IS was done by MS/MS with a turbo ion spray interface operating in positive ion and selective reaction monitoring acquisition mode. The total chromatographic run time was 3.0 min. Flash freezing of the aqueous phase was an added advantage during liquid-liquid extraction, which considerably reduced time and labour. The method was extensively validated for its accuracy, precision, recovery, stability studies and matrix effect. The method was successfully used for bioequivalence study of 40 mg SV tablet formulation in 12 human subjects under fasting condition.