In this study, two simple and accurate LC-MS/MS methods were firstly developed and validated to quantify EVT201, a new partial GABAA receptor agonist used for the treatment of insomnia, and its metabolites comprising M1, M2, M3, M4 and M6 in human urine. The analytes in urine samples were determined after simple dilution, and ideal chromatographic separations were obtained on C18 columns using gradient elution. The assays were performed in MRM mode on AB QTRAP 5500 tandem mass spectrometry (ESI+). The concentration ranges (ng/mL) of analytes in human urine were as follows: EVT201, 1.00 to 36.0; M1, 1.40 to 308; M2, 2.00 to 72.0; M3, 5.00 to 1100; M4, 2.00 to 300; and M6, 2.80 to 420. The methods were fully validated including selectivity, carryover, matrix effect, recovery, linearity, accuracy, precision, dilution integrity and stability, and acceptable criteria were obtained. The methods were successfully applied to a mass balance study of EVT201. The results showed that the total cumulative urinary excretion rate of EVT201 and its five metabolites was 74.25 +/- 6.50%, which suggested that EVT201 had high oral bioavailability, and urinary elimination was its major excretion pathway in human.

Sulfobutyl ether-beta-cyclodextrin sodium salt contained in the marketed intravenous voriconazole injection as a solubilizer may cause harmful accumulations. This study aimed to evaluate the safety, tolerability, and pharmacokinetics (PKs) of two intravenous voriconazole formulations containing excipients from different manufacturers using increasing dose administrations in healthy Chinese volunteers. A randomized, double-blind, placebo-controlled trial was conducted in three cohorts with 42 healthy Chinese volunteers. Each cohort of 14 volunteers was allocated in proportion (8:4:2) to test the formulation, reference voriconazole, or placebo successively by single-dose then multiple-dose administrations of 3, 4, and 6 mg/kg. Forty-one volunteers completed all drug administrations. The pharmacokinetics of test formulations are characterized by high interindividual variability (coefficient of variance of C-max up to 68.0%, AUC(0-tau) up to 70.2%, and nonlinear PKs with a regression coefficient of C-max = 1.31 and AUC(0-tau) = 1.75 in a single dose). In the steady state, R-Auc of the test drug versus reference drug of the 3, 4, and 6 mg/kg dose group were 5.2 and 5.3, 5.6 and 6.3, and 5.8 and 5.5, respectively, and Rc(max) were 2.5 and 2.7, 2.6 and 3.1, and 2.8 and 2.6, respectively. Eighty-three adverse events with 37 transient visual disturbances were mild. PKs with high interindividual variability, nonlinear characteristics, and significant dose-dependent accumulation were comparable between the two formulations. Overall, the safety of the test formulation was acceptable.

Objective: Our objective is to explore the effect of applying cloud video conferencing methods to the informed consent process in an early-phase clinical trial during the COVID-19 pandemic. Methods: All participants who intended to participate in the trial were informed via a cloud video conference before signing the informed consent forms (ICF). Then, the attitudes of the participants with the cloud video conference and their understanding of the trial were evaluated using a questionnaire when they visited to sign the ICF onsite. Results: A total of 165 subjects participated in the cloud video conference process, and 142 visited the site to sign and date the ICFs at the center during the appointment time. The survey showed that nearly 100% of the subjects evaluated the video-based informed consent process as very good or good and gave correct answers to questions about the trial. Furthermore, 136 (95.8%) subjects believed that the knowledge about the trial derived via the video-based informed consent process was consistent with the onsite reality, and 139 (97.9%) subjects expressed their willingness to participate in an informed consent procedure undertaken through an online video conference. Conclusions: The video-based informed consent process achieved the same effects as an onsite informed consent process. The former saves time and cost of transportation for the subject and exhibits good public acceptance; especially in light of the COVID-19 pandemic, this process is conducive for reducing the risk of subject infection due to travel and would also help avoid crowding on site.

Objectives To evaluate the pharmacokinetic properties and safety of empagliflozin, and the bioequivalence of test formulation empagliflozin tablet compared with the brand-name drug Jardiance (reference formulation) after single oral administration under fasting and fed conditions in healthy Chinese subjects. Methods An open-label randomized single-dose two-sequence, two-treatment, two-period crossover study was conducted in healthy Chinese subjects, with 30 subjects under fasting condition and another 30 subjects under fed condition. Under each condition, subjects received a single oral administration of either the test or reference empagliflozin formulation, and then they received a single oral dose of the other formulation after a 7-day washout period. Results A total of 29 subjects under each condition completed the study. The maximum plasma drug concentration, the area under the plasma concentration-time curve (AUC) from 0 to t (AUC(0-t)), and the AUC from 0 to infinity (AUC(0-infinity)) of test formulation and reference formulation was 186.90 +/- 47.21 and 190.60 +/- 40.94 ng/ml, 1303.04 +/- 234.28 and 1267.78 +/- 217.07 ng center dot hour/ml, and 1328.08 +/- 243.84 and 1293.22 +/- 224.82 ng center dot hour/ml under fasting condition, and 151.55 +/- 23.86 and 154.08 +/- 30.40 ng/ml, 1215.65 +/- 197.62 and 1199.26 +/- 186.23 ng center dot hour/ml, and 1241.76 +/- 202.47 and 1225.54 +/- 192.10 ng center dot hour/ml under fed condition, respectively. Conclusions The two formulations of empagliflozin were bioequivalent, and both were generally well tolerated under fasting and fed conditions.

目的 建立测定人血浆中马尼地平浓度的液相色谱-串联质谱法.方法 200μL血浆样品经液液萃取后,使用Phenomenex Synergi 4μHydro-RP 80A色谱柱(150 mm×2.0 mm I.D.),以甲醇-5 mmol/L乙酸铵溶液(含0.3％ 乙酸)为流动相进行梯度洗脱.API 3200型三重四极杆串联质谱仪采用电喷雾离子源 、正离子方式检测 、多重反应监测(MRM)扫描,马尼地平和尼群地平的离子反应分别为质荷比(m/z)611.1→167.3和m/z 361.1→315.2.方法学验证内容包括选择性 、基质效应 、线性范围 、定量下限 、准确度与精密度 、提取回收率 、血浆/溶液样品稳定性.结果 马尼地平和内标尼群地平的保留时间分别约为2.47 min和3.03 min.马尼地平的线性范围为0.1～16.0 ng/mL,低中高浓度质控样品的批内 、相对标准偏差均小于15％,相对误差均在 ±15％ 以内,平均基质效应因子为(85.0±2.8)％,平均提取回收率为(89.2±4.8)％,血浆/溶液样品在不同保存条件下稳定性良好.结论 该方法灵敏耐用,可用于人血浆中马尼地平浓度的测定及马尼地平口服制剂的人体药代动力学研究.

Pharmacokinetics of exogenous strontium (Sr) and bioequivalence of a new oral formulation of strontium ranelate compared with the brand-name drug in healthy Chinese subjects was evaluated. A balanced, randomized, single-dose, two-treatment parallel study was conducted in 36 healthy Chinese subjects. Subjects were randomly allocated into two groups of 18 to receive a single oral dose of test formulation and reference formulation under a fasting state, respectively. Blood samples were collected at 19 designated time points up to 240-h post-dose. Serum concentrations of Sr were quantified by ICP-MS. A total of 36 subjects were enrolled and completed the study. Nine mild adverse events in 6 subjects were reported. The C-max, AUC(0-72 h), AUC(0-t), and AUC(0-infinity) of test and reference formulations shown as mean +/- SD were 6.97 +/- 1.78 and 6.78 +/- 1.80 mu g/mL, 199 +/- 51 and 187 +/- 38 mu g center dot h/mL, 303 +/- 89 and 278 +/- 54 mu g center dot h/mL, and 337 +/- 109 and 305 +/- 60 mu g center dot h/mL, respectively. Two formulations were bioequivalent, and both were generally well tolerated.

Objective To develop a rapid and sensitive liquid chromatography-tandem mass spectrometric(LC-MS/MS) method for the determination of valproic acid in human plasma.Methods After treating human plasma sample by acetonitrile protein precipitation method,the analytes were separated on a Shimpack VP-ODS analytical column(150 mm×2.0 mm I.D,5 μm) with the mobile phase of methanol and 5 mmol/L ammonium acetate (55∶45,v/v)at a flow rate of 0.4 mL/min.Detection was carried out by adopting the multiple reaction monitoring(MRM) scanning mode in the API3200 triple quadrupole tandem mass spectrometer,electrospray ionization source,negative ion mode,selected monitoring ionic reactions were m/z 142.9→m/z 142.9(valproic acid) and m/z 179.0→m/z 179.0(1-sulfonic acid).Results Valproic acid and internal standard 1-sulfonic acid retention time were 3.03 min and 2.38 min respectively.The plasma valproic acid linear range was 0.800-80.0 μg/mL(r>0.99) with the lower limit of quantitation(LLOQ) 0.800 μg/mL.The intra-and inter-batch relative standard deviations(RSD) were both less than 15%,and the relative errors(RE) were within ±15%.The mean extraction recovery rate was(84.1±2.4)%,and the mean matrix effect factor was(104.3±2.0)%.In the stability study,valproic acid was found to be stable in plasma under various storage conditions.Conclusion This method is suitable for the determination of valproic acid in human plasma and human pharmacokinetic study of valproic acid semisodium sustained release tablet.

生物药剂学分类系统将药物按溶解度和渗透性分为4类,在指导新药研发和剂型设计、预测药物体内体外相关性、进行生物豁免研究等方面发挥了非常重要的作用.本文综述了基于生物药剂学分类系统的口服固体速释制剂生物豁免所需溶解度、渗透性和溶出度的接受标准和测定方法,并分类描述了进行过生物豁免研究的药物及其有关资料;建议我国尽快开展和接受生物豁免.

Efonidipine hydrochloride is a new generation dihydropyridine Ca2+ channel blocker designed to inhibit both T-type and L-type Ca2+ channels. Efonidipine possesses a chiral carbon and is clinically administered as a racemate. In the present study, an enantioselective and sensitive LC-MS/MS method of determining efonidipine enantiomers in human plasma was developed and validated to characterize the stereoselective pharmacokinetics. Plasma samples were processed by liquid-liquid extraction (LLE). Chiral separation was optimized on a CHIRALPAK (R) ID column using an isocratic mobile phase of acetonitrile/water (60:40, v/v). Detection was using MS in multiple reaction monitoring (MRM) mode, using the transitions of m/z 6323 -> 91.1 for efonidipine enantiomers, and m/z 493.3 -> 117.2 for cilnidipine (internal standard). The calibration curves were linear over 0.100-20.0 ng/mL for each enantiomer. The lower limit of quantification (LLOQ) for each enantiomer was established at 0.100 ng/mL. Intra- and inter-day precisions were less than 12.1% for each enantiomer in terms of relative standard deviation (RSD), and accuracies were between -5.0% and 5.0% in terms of relative error (RE) for each enantiomer. No chiral inversion was observed during sample storage, preparation procedure and analysis. The validated method was successfully applied to a stereoselective pharmacokinetic study of efonidipine in healthy subjects after oral administration of 40 mg (20 mg x 2) efonidipine hydrochloride tablets. (C) 2016 Elsevier B.V. All rights reserved.

目的 建立测定人血浆和尿液中培拉米韦的LC-MS/MS法.方法 12名中国健康受试者单次静脉滴注培拉米韦三水合物氯化钠注射液,给药剂量为600 mg,采集血浆样本和尿液样本并测定其中培拉米韦的浓度.血浆样本以乙腈沉淀蛋白、尿液样本经直接稀释后,选用Synergi Hydro-RP 80A C18色谱柱(150 mm×2.0 mm,4μm),以甲醇∶0.5％甲酸=35∶65 (V/V)为流动相,流速为0.4 mL· min-1.选用三重四极杆串联质谱仪的多重反应监测(MRM)扫描方式进行监测,电喷雾离子化源,正离子方式.使用WinNonlin 6.3软件计算药动学参数.结果 血浆和尿液中培拉米韦的线性范围分别为0.024 0～60.0 mg·L-1、0.400 ～1 000 mg·L-1;测定血浆中培拉米韦的日内、日间相对标准差(RSD)均小于8.0％,相对误差(RE)在±8.0％的范围以内,测定尿液中培拉米韦的日内、日间RSD均小于4.0％,RE在±10.0％的范围以内;提取回收率较高,且可重现;血浆和尿液样本中的内源性物质不干扰培拉米韦和内标的测定;培拉米韦在各种贮存条件下均较稳定.中国健康受试者单次静脉滴注培拉米韦600 mg后的主要药动学参数如下:ρmax为(41.1±5.3) mg·L-1,AUC0-t为(112.1±13.2) mg·h·L-1,AUC0-∞为(112.3±13.2) mg·h·L-1,t1/2为(3.28±1.15)h.36 h内,培拉米韦的尿液累积排泄率为(90.50±7.38)％.结论 该方法快速、灵敏、专属性强、重现性好,适用于培拉米韦的人体药动学研究.

目的:建立测定人血浆中谷氨酸和精氨酸的方法,以应用于人体药代动力学研究.方法:血浆样本经与丹酰氯衍生化反应后,选用Synergi 4μ Hydro-RP 80A柱(150 mm ×2.0 mm,4μm),以甲醇-10 mmol·L-1乙酸铵(含0.1％甲酸)(50∶ 50)为流动相,流速0.3 mL·min-1,采用API3200型三重四极杆串联质谱仪的多重反应监测(MRM)扫描方式进行监测,电喷雾离子化源,正离子方式,选择监测离子反应分别为m/z 381.0--170.2(谷氨酸丹酰氯衍生化产物)、m/z 408.0--170.3(精氨酸丹酰氯衍生化产物)和m/z 353.0 →157.1(内标D-高丝氨酸丹酰氯衍生化产物).结果:谷氨酸、精氨酸和内标D-高丝氨酸的丹酰氯衍生化产物的保留时间分别为4.62、3.21和4.39 min;血浆中谷氨酸和精氨酸的线性范围均为3.00～300 μg·mL-1(r＞0.99),定量下限(LLOQ)均为3.00 μg·mL-;批内、批间精密度(RSD)均小于15％;准确度(RE)均在±15％的范围以内;谷氨酸和精氨酸平均提取回收率分别为(85.6±3.3)％和(79.9±3.9)％;平均基质效应因子分别为(116.3±4.9)％和(102.4±7.3)％;稳定性试验中,在各种贮存条件下血浆中谷氨酸和精氨酸均较稳定.结论:该方法适用于谷氨酸精氨酸注射液人体药代动力学研究.

ObjectiveTo develop a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination of cefdinir in human plasma and evaluate the bioequivalence of its two granules.MethodsA single oral dose of 100 mg cefdinir test and reference granules were given to 24 healthy male volunteers in a randomized, two-way crossway study. The concentrations of cefdinir in plasma were determined by LC-MS/MS, and the pharmacokinetic parameters were calculated by WinNonlin 6.3 Software, and the bioequivalence of the two preparations was evaluated.ResultsThe linear range for determining cefdinir in plasma samples was 10.0 — 2000 ng/mL(r= 0.999 7), with the lower limit of quantification (LLOQ) of 10.0 ng/mL. The intra- and inter-batch relative standard deviation (RSD) was lower than 6.0%, and relative error (RE) was within ± 4.0%. Degradation degree of cefdinir in human plasma was increased under the room temperature storage with the extension of storage time. The main pharmacokinetic parameters of test and reference preparations were as follows: AUC0-t were (6238.22 ± 1993.74) and (6331.35 ± 1850.42) ng·h/mL; AUC0-∞ were (6 343.68 ± 2070.73) and (6429.76 ± 1901.33) ng·h/mL;Cmax were (1290 ± 391) and (1330 ± 384) ng/mL;tmax were 2.50 (2.00 — 4.50) h and 2.50 (2.00 — 3.50) h;t1/2 were (1.61 ± 0.17) and (1.61 ± 0.17) h, respectively. The geometric mean ratios (GMRs) for AUC0-t, AUC0-∞, andCmax were 97.88% (90% CI, 91.75% — 104.42%), 97.95% (90% CI, 91.76% — 104.56%) and 96.75% (90% CI, 90.43% — 103.52%), respectively.ConclusionThe established method is rapid, sensitive, accurate, selective, reliable, and sufficient for the determination of cefdinir in human plasma, andthe two preparations are bioequivalent.

Abstract Agomelatine is an antidepressant with a unique action mechanism differing from conventional antidepressants. The high inter- and intra-individual variability of agomelatine was previously reported, but no exact data values about the inter- and intra-individual variability in AUC and Cmax were mentioned. The current study aimed to determine and evaluate the inter- and intra-individual variability in AUC and Cmax of agomelatine tablets in Chinese healthy male subjects, providing useful information for designing bioequivalence studies of agomelatine. Each of 12 Chinese healthy male subjects received a 25-mg agomelatine tablet on 2 separate periods, and plasma samples were collected up to 24 h after dose and analyzed for agomelatine. Inter- and intra-individual variability in the pharmacokinetic parameters (Cmax, AUC0–t and AUC0–∞) of agomelatine was assessed. High variations in the plasma concentrations of agomelatine could be observed at each sampling time between the different subjects and in one subject on different periods. The inter-individual CVs of Cmax, AUC0–t and AUC0–∞ were 102.20%, 131.74% and 130.59%, respectively. The intra-individual CVs of Cmax, AUC0–t and AUC0–∞ were 84.34%, 49.61% and 50.83%, respectively. The results showed high inter- and intra-individual variability in the pharmacokinetics of agomelatine in Chinese healthy male subjects, and the intra-individual variability at CV>80% should be considered in the design of bioequivalence studies.

A rapid, sensitive and accurate ICP-MS method using alternate analyte-free matrix for calibration standards preparation and a rapid direct dilution procedure for sample preparation was developed and validated for the quantification of exogenous strontium (Sr) from the drug in human serum. Serum was prepared by direct dilution (1:29, v/v) in an acidic solution consisting of nitric acid (0.1%) and germanium (Ge) added as internal standard (IS), to obtain simple and high-throughput preparation procedure with minimized matrix effect, and good repeatability. ICP-MS analysis was performed using collision cell technology (CCT) mode. Alternate matrix method by using distilled water as an alternate analyte-free matrix for the preparation of calibration standards (CS) was used to avoid the influence of endogenous Sr in serum on the quantification. The method was validated in terms of selectivity, carry-over, matrix effects, lower limit of quantification (LLOQ), linearity, precision and accuracy, and stability. Instrumental linearity was verified in the range of 1.00-500ng/mL, corresponding to a concentration range of 0.0300-15.0μg/mL in 50μL sample of serum matrix and alternate matrix. Intra- and inter-day precision as relative standard deviation (RSD) were less than 8.0% and accuracy as relative error (RE) was within ±3.0%. The method allowed a high sample throughput, and was sensitive and accurate enough for a pilot bioequivalence study in healthy male Chinese subjects following single oral administration of two strontium ranelate formulations containing 2g strontium ranelate.

1.The aim of the study was to evaluate the pharmacokinetics of peramivir after single intravenous (i.v.) doses in healthy Chinese subjects. 2.In a cross-over study, 12 subjects were given 300 and 600 mg peramivir by i.v. infusion. Blood and urine samples were collected at 17 designated time points and 7 designated intervals up to 36 h post-dose. Plasma and urine concentrations of peramivir were quantified by LC-MS/MS. 3.After single i.v. doses of 300 and 600 mg peramivir, Cmax and AUC0-t of peramivir were 21.4 ± 3.7, 41.1 ± 5.3 mgċL(-1) and 55.90 ± 10.62, 112.1 ± 13.2 mgċh L(-1), respectively. Cmax and AUC increased in proportion to the dose. Within 12 h, accumulative urinary recoveries of peramivir after single i.v. doses of 300 and 600 mg peramivir were 84.31 ± 11.75% and 88.10 ± 7.39%, respectively. 4.In healthy Chinese subjects, peramivir displayed linear pharmacokinetics in the range of 300-600 mg, and was primarily excreted via urine as unchanged drug.

Efonidipine hydrochloride is a new generation dihydropyridine calcium channel blocker designed to inhibit both T-type and L-type calcium channels. For the first time, a simple and robust LC-MS/MS method was developed for the determination of efonidipine in human plasma over the range of 0.100-20.0ng/mL. Efonidipine was extracted from plasma by an LLE procedure, separated by LC and detected by MS/MS in positive mode ESI. The method was validated for selectivity, carryover, sensitivity, extraction recovery, matrix effects, linearity, accuracy and precision, dilution integrity and stability studies. The calibration curves were linear over 0.100-20.0ng/mL (r≥0.9980). The lower limit of quantification (LLOQ) was established at 0.100ng/mL. Intra- and inter-day precisions (LLOQ, low-QC, mid-QC, high-QC and ultra-high QC) were less than 12.5% in terms of relative standard deviation (RSD), and accuracies were between -5.0% and 5.0% in terms of relative error (RE). Matrix effect was acceptable (105.6-110.2%) and extraction recovery was reproducible (85.8-91.3%, RSD≤10.0%). Efonidipine was stable in the investigated conditions. The method was applied to the pharmacokinetics of efonidipine in human subject.

The gender differences in pharmacokinetics of a combination tablet of niacin extended-release/simvastatin were evaluated in healthy Chinese volunteers. Thirty-six healthy male and female volunteers were enrolled in the study receiving a single oral dose of niacin extended-release/simvastatin 1,000/20 mg. The results indicated that the systemic exposure of simvastatin hydroxy acid and the total urine excretion of niacin were significantly higher for females compared with those for males, and the T max of niacin in plasma was significantly shorter for males than that for females. There were no significant differences in the systemic exposure of simvastatin, niacin, and NUA in plasma between males and females.

Objective:To evaluate the effect of glucose on the bioavailability of metformin hydrochloride tablets.Methods:Twenty healthy male subjects were given a single oral dose of 500 mg metformin hydrochloride tablet in fasting condition with warm boiled water or 20% glucose aqueous solution.Venous blood glucose levels from pre-dosing to 4 h post-dosing were monitored by hexokinase method using automatic biochemical analyzer.Plasma concentrations of metformin up to 24 h post-dosing were determined by LC-MS/MS.The pharmacokinetic parameters were calculated by DAS software.The relative bioavailability(F) of metformin hydrochloride tablet given with 20% glucose solution compared with that administered with warm boiled water was calculated,and bioequivalence was investigated to evaluate the effect of glucose on bioavailability of metformin hydrochloride tablets.Results:Venous blood glucose level of healthy subjects significantly decreased at 1.5~4 h post-dosing of metformin hydrochloride tablets in fasting condition with warm boiled water,while significantly increased after being administered with 20% glucose solution.The pharmacokinetic parameters of metformin hydrochloride tablets administered with warm boiled water and 20% glucose solution were as follows:Tmax(2.20±0.94)and(2.08±1.02) h,Cmax(1.00±0.34)and(0.960±0.339) ng·mL-1,t1/2(3.25±0.62)and(3.18±0.74) h,AUC0~t(5.72±1.50)and(5.58±1.35) ng·h·mL-1,and AUC0~∞(5.77±1.51)and(5.64±1.34) ng·h·mL-1,respectively.Compared with being administered with warm boiled water,the F0~t and F0~∞ of metformin hydrochloride tablets administered with 20% glucose solution were(100.2±22.3)% and(100.4±22.1)%,respectively,which indicated that the two administration ways were bioequivalent.Conclusion:The bioavailability of metformin hydrochloride tablets is not affected by glucose.In order to prevent hypoglycemic reaction,it is suggested that oral antidiabetic drugs including metformin hydrochloride be administered with glucose solution in bioequivalence studies,and glucose solution be given to subjects within a certain period after dosing.

OBJECTIVE:To develop method for the determination of amlodipine in human plasma,and to evaluate bioequivalence of 2 kinds of Amlodipine besylate tables in healthy volunteers.METHODS:After liquid-liquid extraction,the samples were separated on Zorbax SB-C 18 Narrow Bore column with mobile phase consisted of methanol-10 mmol/L ammonium acetate(90:10,V/V)at the flow rate of 0.3 ml/min.Detection was carried out by electrospray positive ionization mass spectrometry in type API3200 multiple reaction monitoring(MRM)mode.The MRM transitions of m/z 409.2→m/z 238.2 and m/z 256.2→m/z 167.3 were used to quantify amlodipine and diphenhydramine(I.S.),respectively.The bioequivalence of test preparation and reference preparation of Amlodipine besylate tablets in 24 healthy volunteers after oral administration were investigated in a randomized,two-periods cross-over study.RESULTS:Amlodipine and I.S.were eluted at 2.79 min and 2.43 min,respectively.The linear range of amlodipine were 0.10-10.0 ng/ml(r=0.999 7)with the lowest quantitation limit of 0.10 ng/ml.Intra-day and inter-day RSDs were both less than 15%;relative errors(RE)were within ±15%.The mean extraction recovery was(84.7±5.5)%,and the mean matrix effect factor was(76.5±8.4)%.The relative bioavailability of test preparation to reference preparation was(105.8±20.9)% according to AUC 0-120 h.CONCLUSIONS:The method is rapid,sensitive,selective and reproducible,and it is suitable for the determination of amlodipine in human plasma and bioequivalence study of Amlodipine besylate tablets in healthy volunteers.Two preparations are bioequivalent.

Objective: To investigate the pharmacokinetics of rivastigmine tartrate in healthy Chinese volunteers, and evaluate the bioequivalence between its domestic tablet(test formulation) and imported capsule(reference formulation). Methods: The plasma concentrations of rivastigmine were determined using LC-MS/MS method in 20 healthy Chinese volunteers after oral administration of rivastigmine formulation. The main pharmacokinetic parameters of rivastigmine and bioequivalence between the two formulations were calculated by DAS 2. 1. 1. The separation was achieved on an Agilent ZORBAX SB-C18 column(150 mm × 2. 1 mm,5 μm),the mobile phase consisted of methanol-10 mmol·L-1ammonium acetate containing 0. 1% formic acid(50 ∶ 50) at a flow rate of 0. 3 mL· min-1,and the column temperature was 35 ℃. ESI source was applied and operated in positive ion mode and multiple reaction monitoring(MRM). The ion combination of m/z 251. 2→206. 3 and m/z 275. 2→230. 2 was used to qualify rivastigmine and chlorpheniramine respectively. Results: The AUC 0-t was(14. 36 ± 9. 61) and(13. 56 ± 8. 88) ng·h·mL-1,C max was(8. 03 ± 4. 01) and(7. 60 ± 3. 37) ng ·mL-1,T max was(0. 75 ± 0. 31) and(0. 70 ±0. 26) h,and t 1/2 was(1. 12 ± 0. 24) and(1. 13 ± 0. 24) h for the test and reference formulations,respectively. The relative bioavailability of the test formulation was(107. 0 ± 16. 2) %. Conclusion: The results demonstrate that the test and reference formulations are bioequivalent,and there is no significant difference in the rate or extent of absorption after oral administration.