目的 探索石杉碱甲在中国老年受试者体内的药动学特点和安全性.方法 14例无认知功能障碍的中国老年受试者(年龄60～80岁)接受单次口服石杉碱甲0.1 mg,在给药后48 h内收集血液和尿液样本.采用液相色谱-串联质谱(LC-MS/MS)法测定生物样品中药物浓度,以获得药动学参数.在整个研究过程中,对受试者进行安全性指标和不良事件监测.结果 老年受试者单次口服石杉碱甲0.1 mg后主要药动学参数:峰浓度(Cmax)(0.92±0.28)ng·mL-1,峰时间(tmax)(2.61±1.67)h,血浆浓度-时间曲线下面积(AUC(0-72h))(15.12±4.73)ng·h·mL-1,AUC(0-∞)(16.99±4.92)ng·h·mL-1,消除半衰期(t1/2)(14.38±3.87)h,48 h累计尿液药物排泄率为34.76％.1例受试者(7.1％)发生与研究药物可能无关的轻度不良事件.结论 石杉碱甲在中国老年受试者中有良好的耐受性.相比非老年健康受试者,老年受试者中石杉碱甲的吸收和消除过程相对更缓慢,暴露程度更高.

目的 研究富马酸喹硫平缓释片仿制药与原研药在中国健康受试者中单剂量空腹和餐后条件下给药的生物等效性.方法 用单中心、开放、随机、单次给药、两制剂、两周期交叉设计,共纳入68例(空腹试验36例,餐后试验32例)成年男性和女性受试者随机交叉给药.分别单次口服受试制剂和参比制剂200 mg,用液相色谱-串联质谱(LC-MS/MS)法测定血浆中喹硫平的浓度.用SAS V9.4软件计算主要药代动力学参数.结果 空腹组的富马酸喹硫平缓释片受试制剂和参比制剂主要药代动力学参数如下:AUC0-t分别为(2432.45±859.54)和(2368.00±792.38)ng·mL-1·h,AUC0-∞分别为(2516.56±864.19)和(2461.20±803.72)ng·mL-1·h,Cmax分别为(206.88±92.00)和(207.16±109.88)ng·mL-1,tmax分别为5.25和4.50 h,t1/2分别为(6.97±2.43)和(7.26±2.13)h.餐后组的富马酸喹硫平缓释片受试制剂和参比制剂主要药代动力学参数如下:AUC0-t分别为(2774.99±1077.62)和(2856.20±1180.25)ng·mL-1·h,AUC0-∞分别为(2840.63±1076.46)和(2916.44±1174.10)ng·mL-1·h,Cmax分别为(398.78±142.90)和(373.15±142.99)ng·mL-1,tmax分别为5.50和5.00 h,t1/2分别为(4.41±0.63)和(4.68±0.96)h.在空腹及餐后条件下,受试制剂与参比制剂主要药代动力学参数的90％置信区间均在80.00％ ～125.00％.结论 在空腹及餐后条件下,中国健康成年受试者单次口服富马酸喹硫平缓释片仿制药与原研药具有生物等效性.

目的 研究吲达帕胺片仿制药与原研药在中国健康受试者中单剂量空腹给药的药代动力学和生物等效性,为临床使用和一致性评价提供依据.方法 采用开放、随机、单次口服给药、两制剂、两周期交叉设计,共纳入26名健康受试者,随机分为2组,分别单次空腹口服吲达帕胺片受试制剂与参比制剂2.5 mg,给药前和给药后按时采集静脉血,以超高效液相色谱-串联质谱(UPLC-MS/MS)法测定全血中吲达帕胺的浓度,随后用SAS9.4软件计算药代动力学参数,评价生物等效性.结果 吲达帕胺片受试制剂和参比制剂后的主要药动学参数如下:Cmax分别为(114.28±17.38)μg·L-1和(96.27±13.36)μg·L-1;AUC0-t分别为(1746.80±297.16)μg·L-1·h和(1717.94±77.49)μg·L-1·h;AUC0-∞分别为(1861.97±295.10)μg·L-1·h和(1835.28±265.85)μg·L-1·h;Tmax(中位数)分别为2.0 h和2.0 h;T1/2分别为(13.99±1.71)h和(14.21±1.78)h.2种制剂的Cmax、AUC0-t和AUC0-∞经对数转换后90％的置信区间分别为113.00％ ～124.13％,99.49％ ～103.67％,99.00％ ～103.57％.结论 国产吲达帕胺片和进口吲达帕胺片药代动力学生物等效性.

Aim: Our preliminary results show that huperzine A, an acetylcholinesterase inhibitor used to treat Alzheimer's disease (AD) patients in China, exhibits different pharmacokinetic features in elderly and young healthy subjects. However, its pharmacokinetic data in elderly subjects remains unavailable to date. Thus, we developed a population pharmacokinetic (PPK) model of huperzine A in elderly Chinese people, and identified the covariate affecting its pharmacokinetics for optimal individual administration.Methods: A total of 341 serum huperzine A concentration records was obtained from 2 completed clinical trials (14 elderly healthy subjects in a phase I pharmacokinetic study; 35 elderly AD patients in a phase II study). Population pharmacokinetic analysis was performed using the non-linear mixed-effect modeling software Phoenix NLME1.1.1. The effects of age, gender, body weight, height, creatinine, endogenous creatinine clearance rate as well as drugs administered concomitantly were analyzed. Bootstrap and visual predictive checks were used simultaneously to validate the final population pharmacokinetics models.Results: The plasma concentration-time profile of huperzine A was best described by a one-compartment model with first-order absorption and elimination. Age was identified as the covariate having significant influence on huperzine A clearance. The final PPK model of huperzine A was: CL (L/h)= 2.4649*(age/ 86)((-3.3856)), K-a= 0.6750 h(-1), V (L)= 104.216. The final PPK model was demonstrated to be suitable and effective by the bootstrap and visual predictive checks.Conclusion: A PPK model of huperzine A in elderly Chinese subjects is established, which can be used to predict PPK parameters of huperzine A in the treatment of elderly AD patients.

目的 研究两种氯吡格雷制剂药动学及在健康人体生物等效性.方法 按双周期交叉试验设计,48例健康男性受试者单剂量口服氯吡格雷受试制剂和参比制剂75 mg后,采用液相质谱-串联质谱(LC-MS/MS)的方法测定血浆中氯吡格雷的浓度,经DAS2.0软件统计,计算药动学参数及相对生物利用度,判定两制剂是否等效.结果 受试制剂和参比制剂的主要药动学参数,氯吡格雷的t1/2分别为(3.31±2.34)和(4.02±2.98)h,ρmax分别为(2.15±5.27)和(1.66±2.91)μg· L-1,tmax分别为(0.79±0.36)和(0.90±0.47)h,AUC0-t (2.29±3.61)和(2.44±3.96) μg·h·L-1.以氯吡格雷成分计,相对生物利用度为(113.8±90.6)％.结论 两种氯吡格雷制剂具有生物等效性.

AIM To study the pharmacokinetics of enalapril-felodipine extended release tablet after a single-dose and multi-dose oral administration in Chinese healthy volunteers,and to evaluate the extended- release characteristics of felodipine in this test combined preparation.METHODS Eleven healthy male volunteers were randomly administered the test and reference formulation preparations in a single-dose and multi-dose, under two-way crossover design.Serum felodipine,enalapril and the active metabolite enalaprilat concentrations were determined by a liquid chromatography-tandem mass spectrometry(LC-MS/MS) method, and the pharmacokinetic parameters were calculated by DAS 2.0 program.RESULTSρ_(max),t_(max),AUC_(0-t) of test and reference tablets after single dose were as follows:(1.8±s 1.0) vs.(2.2±1.5)μg·L~(-1),(8±4) vs.(4.1±2.0) h,(38±24) vs.(28±22)μg·h·L~(-1) in felodipine;(44±16) vs.(38±12)μg·L~(-1)(0.77±0.18) vs. (1.2±0.6) h,(70±22) vs.(76±20)μg·h·L~(-1) in enalapril,and(23±12) vs.(21±9)μg·L~(-1),(4.4±1.1) vs.(4.5±0.9) h,(211±78) vs.(215±79)μg·h·L~(-1) in enalaprilat.The steady state concentrations (ρ_(ss-av)) and fluctuate degree(DF) of test and reference tablets after multi-dose were as follows:(1.8±1.3) vs. (1.5±0.9)μg·L~(-1) and(0.96±0.24) vs.(2.7±1.4) respectively in felodipine,and(10±3) vs.(10±3)μg·L~(-1),(2.8±0.5) vs.(2.8±0.5) in enalaprilat.CONCLUSION Comparing with the reference tablet,felodipine in the test combination tablet shows extended release characteristics and the pharmacokinetic process of enalapril and the active metabolite enalaprilat reveals as basically similar in healthy male volunteers.

AIM To establish a LC-MS/MS method for the determination of enalapril and its metabolite enalaprilat in human serum. METHODS After addition of phentolamine mesilate (internal standard, IS) into serum sample, methanol was directly used for protein precipitation. The chromatographic separation was performed on Varian Polaris C_(18)-Ether (50 mm × 2.1 mm, 5 μm) column with a mobile phase of methanol : 0.5% formic acid solution (40 : 60, V/V) with a flow rate of 0.3 mL·min~(-1). The scanning method was carried out in positive ionization by multiple reaction monitoring mode (MRM) . The selection of mass transition pair chanels of m/z 377.2→234.1, m/z 349.3→206.1 and m/z 282.4→211.8 were used to detect enalapril, enalaprilat and internal standard, respectively. RESULTS The linear concentration ranges of the calibration curves for enalapril and enalaprilat were both as 0.25 - 200 μg·L~(-1). The lowest limit of quantitation for both was 0.25 μg·L~(-1). The retraction rate was more than 90%. Intra-day RSD and inter-day RSD were both less than 10%. CONCLUSION The pretreatment of this method is simple and quick, with high specificity and sensitively, and low sampling volume, coinciding with cost low, and suitable for the need of pharmacokinetics researches for enalapril and its metabolite enalprilat.

AIM To establish a LC-MS/MS method for determination of rosiglitalizone in human serum. METHODS After addition of glibenclamide ( internal standard,IS) into serum sample,the analyte was processed by protein precipitation. The chromatographic separation was performed on Gemini 5u C18 110A (2.0 mm×50 mm,5 μm) column with a mobile phase of 10 mmol·L-1 of ammonium acetate aqueous solution-acetonitrile (40∶60,V∶V) at a flow rate of 0.3 mL·min-1. The protonated ions of analyte were detected in positive ionization by multiple reaction monitoring modes (MRM). The mass transition pairs of m/z 358.4→ 135.2 and m/z 494.5→369.2 were used to detect rosiglitalizone and internal standard,respectively,through MRM. RESULTS The linear concentration range of the calibration curves for rosiglitalizone was 2.5-640 μg· L-1. The lowest limit of quantitation was 2.5 μg·L-1. Within-day RSD and between-day RSD were less than 15%. CONCLUSION The method of LC-MS/MS is sensitive,accurate,specific and suitable for the pharmacokinetic study of rosiglitalizone.

Objective:To establish a liquid chromatography-tandem mass spectrometry(LC-MS/MS)method for the determination of flurbiprofen in human serum.Method:The serum samples were precipitated with methanol.The drug was determinated by LC-MS/MS using electrospray ionization.Flurbiprofen and its internal standard(IS)in- domethacin were detected on multiple reaction monitoring(MRM)by the transitions from the precursor to the prod- uct ion(m/z 243.3/198.8 and m/z 356.3/312.0).The retention time of these two analytes were 0.9 min and 1.6 rain.An API3000 tandem mass spectrometer and an Shimadzu liquid chromatograph were used for all analyses.The analytical column was a Gemini C_(18)scolumn(50 mm×2.1 mm,5 μm).The mobile phase,acetonitrile-water(18: 82),was used at a flow rate of 0.3 mL·min~(-1).The injection volume was 3 μL and the total run time was 3.0 min. Results:Calibration curve had good linearity in the range of 0.05-50 μg·mL~(-1)(r=0.9995).The intra-and in- ter-day precision(RSD)were all less than 15% and the accuracy was within 99.6-101.5%.Conclusion:The established LC-MS/MS method is shown to be sensitive,accurate and simple for the determination of flurbiprofen in human serum.It is suitable for the pharmacokinetics and bioavailability study of flurbiprofen.

AIM:To develop a LC-MS/MS method for determination of amlodipine besylate in human serum.METHODS:After addition of diphenhydramine(internal standard,IS),the analyte was isolated by protein precipitation.The chromatographic separation was performed on Atlantis C_(18)(100 mm×2.1 mm,3μm) column with a mobile phase of 0.1% formic acid acetonitrile-0.1% formic acid water(42:58,V:V)at a flow rate of 0.25 mL·min~(-1).The deprotonated ion of analyte was detected in negative ionization by multiple reaction monitoring mode(MRM).The mass transition pairs of m/z 409.1→238.1 and m/z 256.3→167.0 were used to detect amlodipine besylate and internal standard,respectively.RESULTS:The calibration curves were linear over the ranges of 0.2-32μg·L~(-1).The lower limit of quantification was 0.2μg·L~(-1).The extraction recovery was more than 95%.The intra-day RSD and inter-day RSD were less than 15%.CONCLUSION:The method is sensitive,accurate,convenient and suitable for the pharmacokinetic study of amlodipine besylate tablets.