来氟米特在中国健康人群中的群体药动学研究

目的：建立来氟米特口服给药在中国健康受试者体内的群体药动学模型,探讨其药动学特征及可能的影响因素。方法：21名健康男性受试者参与本次研究,应用Phoenix NLME（Vision 8.0）软件中的群体模块分析来氟米特口服给药后其代谢产物的血药浓度数据,估算相关药动学参数及其变异情况。结果：来氟米特活性代谢产物特立氟胺在健康志愿者中符合一级吸收的一室模型。吸收速率常数K_a、分布容积V、药物清除率CL的群体典型值分别为0.691 h^-1、12.843 L和0.031 L·h^-1。协变量筛选结果显示,BMI对分布容积V有显著影响（P<0.01）。结论：本研究成功建立了来氟米特在中国健康人群中的群体药动学模型,最终模型可对个体药代参数做出精确的估计,BMI对分布容积V有显著影响。     

8名健康志愿者静滴头孢西丁的药物动力学

目的:测定国产头孢西丁iv gtt在人体内的药物动力学.方法:8例健康志愿者,恒速iv gtt 2g国产头孢西丁,用高效液相色谱外标法测定国产头孢西丁在正常人体内的血药浓度.结果:头孢西丁血浓峰值为(92.07±21.95)μg/ml,T_(1/2β)为(54.29±8.01)min,Cl为(0.38±0.08)L/min,Vd为(13.27±3.69)L.AUC为(90.34±19.59)μg/(h·ml),K_(10)为(0.029±0.0036)L/min.各项动力学参数与国外文献报道基本相符.结论:头孢西丁国产与进口产品的体内处置过程相同.     

精氨洛芬片剂与颗粒剂在健康受试者体内的生物等效性

目的 研究精氨洛芬(非甾体抗炎药)片剂与颗粒剂在中国健康志愿者体内的生物等效性.方法 20名健康男性受试者分别随机交叉口服精氨洛芬片(试验制剂)及其颗粒(参比制剂)0.4 g,用HPLC-UV法测定给药后不同时间点的血浆布洛芬浓度;用DAS程序对试验数据进行统计处理,评价2种制剂的生物等效性.结果 试验制剂和参比制剂的药代动力学参数如下:Cmax分别为(50.60±9.12)、(50.53±8.58)nag·L-1,tmax分别为(0.51±0.20)、(0.34±0.11)h,AUC0～t分别为(118.63±21.42)、(115.75±20.23)mg·h·L-1,AUC0～∞分别为(121.18±22.18)、(118.55±21.83)mg·h·L-1.试验制剂与参比制剂AUC0-t之比和Cmax之比的90%可信区间分别为97.5%～107.6%和93.3%～107.2%.结论 试验制剂和参比制剂吸收程度等效(AUC0-t,AUC0-∞和Cmax均生物等效性);但吸收速度不等效(tmax不等效).     

The pharmacokinetics of orally administered fudosteine in healthy Chinese volunteers.

The pharmacokinetics of fudosteine in healthy Chinese volunteers was investigated for the first time after single- and multiple-dose administration. Five male and five female volunteers were enrolled in this study. Each subject received 400 mg fudosteine capsules (the therapeutic dose) on day 1 after overnight fasting for the single-dose study and three times daily oral administration (400 mg) for 5 consecutive days until the sixth morning for the multiple-dose study. Serial blood samples were collected at specified time intervals up to 16 hours following the first and last doses of fudosteine. Plasma harvested from the blood was separated and analyzed for fudosteine levels by a validated high-performance liquid chromatography-electrospray ionization mass spectrometry (HPLC/ESI/MS) method employing percolumn derivatization with 9-fluorenylmethyl chloroformate (FMOC-Cl). Noncompartmental analysis was used for the calculation of the total area under the plasma concentration-time curve (AUC) from time zero to time infinity and the terminal half-life (t1/2) of fudosteine. The pharmacokinetic parameters for single- and multiple-dose administration were estimated as follows: Cmax amounted to 10.13+/-4.39 microg/mL and 11.75+/-6.51 microg/mL, tmax to 0.69+/-0.36 h and 0.53+/-0.12 h and t1/2 to 2.33+/-0.63 h and 2.40+/-0.37 h, respectively. No significant differences were found between single- and multiple-dose oral administration, although gender differences were observed.     

A comparative study of the pharmacokinetics of ibuprofen arginate versus dexibuprofen in healthy volunteers

OBJECTIVE: Ibuprofen arginate is a salt formulation of ibuprofen designed to reach target concentrations rapidly. The primary objective of this study was to compare the 12-h pharmacokinetic profile of S(+)-ibuprofen following administration of single doses of ibuprofen arginate (600 mg) and dexibuprofen (400 mg) in healthy volunteers. METHODS: Twenty-four volunteers were recruited into an open-label, randomised, two-period, single-centre study with crossover design. RESULTS: Both treatments were well tolerated. Ibuprofen arginate and dexibuprofen showed similar bioavailability for S(+)-ibuprofen. Compared with dexibuprofen, ibuprofen arginate demonstrated a 45% higher maximum concentration (C(max)), and a time to peak concentration (T(max)) 2 h sooner. CONCLUSION: Ibuprofen arginate approaches maximum concentrations of S(+)-ibuprofen faster and higher than dexibuprofen.     

Population pharmacokinetics of arginine glutamate in healthy Chinese volunteers

1.?The present study developed population pharmacokinetic models of arginine and glutamate in healthy Chinese volunteers. Two nonlinear mixed-effect models were developed using NONMEM® software (ICON Development Solutions, Ellicott City, MD) to describe the pharmacokinetic properties and to assess the relevant parameters as well as the inter-individual variability. The potential covariates were screened using stepwise approach and the stability and predictive capability of the models were performed using bootstrap and visual predictive check.

2.?The concentration time curves of arginine and glutamate were best described by a first-order elimination two-compartment model and a nonlinear elimination one-compartment model, respectively. The final parameter estimation of arginine for CL was 44.1?L/h. Q, V₁ and V₂ were 23?L/h, 20.3?L and 46?L, respectively. The final parameter estimation of glutamate for V_max and K_m were 18.8?mg/h and 77.2?mg/L, respectively. V for low dose and high dose was 23.1?L and 36.3?L, respectively.

3.?For arginine, weight was significant covariate on the apparent distribution volume of peripheral compartment. The gain in weight remarkably increases V_2. For glutamate, dose as a significant covariate on the apparent distribution volume was included, subjects received high dose (20?g) have remarkably higher V compared to subjects received low dose (10?g).     

Stereoselective pharmacokinetics of propafenone and its major metabolites in healthy Chinese volunteers.

The stereoselective pharmacokinetics of propafenone (PPF) and its active metabolite 5-hydroxypropafenone (5-OHP) as well as their glucuronide and sulfate conjugates have been investigated, in order to clarify the relationship between metabolism and stereoselective disposition of PPF in humans. After oral administration of 300 mg racemic PPF hydrochloride to 10 healthy Chinese subjects, the areas under the plasma concentration-time curves (AUCs) for (S)-PPF were significantly higher (S/R ratio, 1.50+/-0.17) and the apparent oral clearance significantly lower (S/R ratio, 0.68+/-0.07) than those parameters for (R)-PPF. In contrast, the AUCs of PPF glucuronide (PPF-G) were lower for (S)-PPF-G than for the (R)-enantiomer (S/R ratio, 0.83+/-0.12). The partial clearance of (S)-PPF by glucuronidation pathway was lower than that of (R)-PPF and the enantiomeric ratio was 0.62+/-0.04. The t(max) values of PPF glucuronide diastereoisomers showed no statistically significant differences between each other, but were much shorter than the corresponding values of the parent drug, implying that glucuronidation may be the 'first-choice' pathway in presystemic metabolism of PPF. Glucuronidation of 5-OHP favored the (S)-enantiomer, whereas the sulfation showed a large preference for the (R)-enantiomer. After beta-glucuronidase hydrolysis, no significant differences were observed in AUCs between 5-OHP enantiomers (including unconjugated and conjugated 5-OHP). The results suggest that the significant difference in disposition between PPF enantiomers may be, at least in part attributed to stereoselective metabolism in the glucuronidation pathway.     

Stereoselectivity of ibuprofen metabolism and pharmacokinetics following the administration of the racemate to healthy volunteers

1. The stereoselective metabolism and pharmacokinetics of the enantiomers of ibuprofen have been investigated following the oral administration of the racemic drug (400 mg) to 12 healthy volunteers.2. The stereochemical composition of the drug in serum, both total and unbound, and drug and metabolites, both free and conjugated, in urine were determined by a combination of the direct and indirect chromatographic procedures to enantiomeric analysis. 3. The oral clearance of (S)-ibuprofen was significantly greater than that of the R-enantiomer (74.5 +/- 18.1 versus 57.1 +/- 11.7 ml min(-1); p < 0.05) and the clearance of (R)-ibuprofen via inversion was ca two fold that via alternative pathways. 4. Some 74.0 +/- 9.6% of the dose was recovered in urine over 24 h as ibuprofen, 2-hydroxyibuprofen and carboxyibuprofen, both free and conjugated with glucuronic acid. Analysis of the stereochemical composition of the urinary excretion products indicated that 68% of the dose of (R)-ibuprofen had undergone chiral inversion. 5. Metabolism via glucuronidation and both routes of oxidation, showed enantio-selectivity for (S)-ibuprofen, the enantiomeric ratios (S/R) in partial metabolic clearance being 7.1, 4.8 and 3.4 for formation of ibuprofen glucuronide, 2-hydroxyibuprofen and carboxyibuprofen respectively.6. Modest stereoselectivity was observed in the formation of (2'R, 2R)- and (2'S, 2S)-carboxyibuprofen in comparison to the alternative diastereoisomers, the ratios in formation clearance being 1.6 and 1.2 respectively.     

注射用法罗培南钠在健康人体的耐受性及其连续给药的药代动力学

目的 确定注射用法罗培南钠(碳青霉烯类抗生素)最大耐受剂量及其连续给药的药代动力学研究.方法 58名健康受试者分别单次静滴注射用法罗培南钠100、200、300、450、600、800 mg及连续静滴给药每次200、300mg,每日3、2次,连续滴注7天.用HPLC法测定连续静滴注射用法罗培南钠200 mg组受试者血浆及尿中法罗培南的浓度.结果 单次450 mg组和连续200、300 mg组,各1人血清ALT、AST升高外;其余受试者无任何不良反应发生.连续多剂量静滴法罗培南钠200 mg后,其药代动力学参数:tmax为(1.00±0.00)h;Cmax为(15.80±3.96)μg·mL-1;t1/2为(1.07±0.27)h;CL/F为(0.15±0.03)L·kg·h-1;Vd/F为(0.23±0.07)L·kg-1;Cav为(2.81±2.96)μg·mL-1;DF为(6.55±5.47);AUC0-t为(24.00±6.23)μg·h·mL-1;AUC0-∞为(23.70±6.27)μg·h·mL-1.其12 h累积尿药排泄率为40.49%.结论 其最大耐受剂量为800 mg;推荐Ⅱ期临床剂量为每次200mg,每日3次.     

Amlodipine pharmacokinetics in healthy volunteers

In the present study we investigated the pharmacokinetics and comparative bioavailability of three oral doses of amlodipine in 12 healthy male volunteers. A randomized, open-label, three period crossover study design was employed. Each subject received, on three separate occasions a single oral dose of 2.5, 5 and 10 mg amlodipine. Standing diastolic blood pressure was reduced by 1.1, 4.8 and 8 mmHg six hours after 2.5, 5 and 10 mg amlodipine, respectively. There were no significant changes in pulse rate, nor on the EKG. The curves for the mean plasma concentrations versus time for the three doses showed parallel time-courses. Highly significant positive correlations were observed between dose and AUC (0-72 hrs) and between dose and Cmax. However, dose corrected AUC and Cmax were 10-20% lower with 2.5 mg, than with 5 and 10 mg. Peak levels were achieved 5.6 to 6.4 hours postdose. Half lives were 31.2, 33 and 36.8 hours for 2.5, 5 and 10 mg respectively. Headache was the most common side effect, and was more frequently observed with the highest dose. In summary, linear relationships were found between the dose and the plasma levels of amlodipine. Decreases in standing diastolic blood pressure were also dose related. Because of its long half-life and gradual absorption, amlodipine should be effective in lowering blood pressure given once daily and the incidence of side effects due to rapid absorption should be minimized.     

中国健康志愿者单次口服法罗培南的药动学研究

目的:通过健康志愿者口服法罗培南进行药动学研究,了解药物在人体内分布、消除规律,为制定合理给药方案提供依据。方法:选择9名健康成人按拉丁方随机分组,分别单剂口服100,200,300 mg三个剂量的法罗培南后,应用微生物法测定血药和尿药浓度,采用3P87软件进行数据处理,求出药动学参数。结果: 血清和尿液中法罗培南分别在0．05-6．4 mg·L-1浓度范围内呈良好的线性关系,日内、日间变异系数及回收率均符合临床药动学研究的要求。受试者单剂口服法罗培南100,200,300 mg后,药-时曲线符合二室模型, 主要药动学参数cmax分别为(2．2±s 0．4),(3．8±1．0),(6．0±0．5)mg·L-1;t1/2β为(0．72±0．22),(0．67±0．24), (0．92±0．19)h;AUC分别为(3．4±1．0),(6±3),(8．8±1．5)mg·h·L-1。24 h尿药累积排泄率分别为(2．1± 0．7),(3．2±1．0),(4．2±0．7)％。结论:法罗培南药-时曲线符合二室模型,cmax和AUC与剂量成正比,而t1/2β基本相同,该药具有线性动力学特征。     

卢帕他定片在中国健康人体的药动学

目的研究卢帕他定片在中国健康人体的药动学特征。方法以卡马西平为内标,色谱柱为inspire C18(2)(150 mm×4.6 mm,5μm),以乙腈:2 mmol·L-1乙酸铵溶液(65:35,V/V)为流动相,流速:0.8 mL·min~(-1);质谱检测卢帕他定和内标卡马西平离子对分别为m/z 416.1→282.1,237.2→194.1。36名健康受试者随机分为低、中、高3个剂量组,每组12人(男女各半),分别单次口服卢帕他定片10 mg、20 mg、40 mg,采用液相色谱-串联质谱法测定给药后不同时间点血浆中卢帕他定的浓度并计算药动学参数。结果人血浆中卢帕他定的最低定量限为0.05μg·L~(-1),在0.05～40μg·L~(-1)范围内线性关系良好,批内及批间精密度(RSD)均小于15%。主要药动学参数如下:ρ_(max)分别为(16.88±8.10)、(30.27±12.10)和(63.87±27.49)μg·L~(-1);t_(max)分别为(0.94±0.39)、(1.00±0.00)和(0.88±0.38)h;t_(1/2)分别为(11.46±3.01)、(8.42±1.65)和(9.06±2.30)h;AUC_(0-t)分别为(46.84±22.15)、(86.16±19.22)和(189.91±59.52)h·μg·L~(-1);AUC_(0-∞)分别为(50.00±23.83)、(88.53±19.49)和(196.13±60.87)h·μg·L~(-1)。结论低、中、高3个剂组中卢帕他定在人体内的AUC_(0-t),AUC_(0-∞)和ρ_(max)均与剂量呈线性关系。     

氨氯地平在中国健康志愿者体内的群体药动学研究

氨氯地平用以治疗高血压和心绞痛的药物,属于第三代双氢吡啶类钙通道阻滞剂.本研究对来自3个氨氯地平生物等效性试验的60个健康志愿者数据进行氨氯地平的群体药代动力学分析.数据及协变量用非线性混合效应模型NONMEN拟合分析.一级吸收的二室模型用以拟合氨氯地平血药浓度数据.在建模过程中没有找到显著的协变量.个体内(残余)变异用变异系数表示,为18.7％.CL,V2,V3和Ka的个体间变异分别为27.3％,26.6％,49.9％和65.7％.V3和Ka的个体间变异相对较高(＞40％),可能因为氨氯地平吸收和处置过程中的基因变异所导致.     

Stereoselectivity of ibuprofen metabolism and pharmacokinetics following the administration of the racemate to healthy volunteers

1. The stereoselective metabolism and pharmacokinetics of the enantiomers of ibuprofen have been investigated following the oral administration of the racemic drug (400?mg) to 12 healthy volunteers. 2. The stereochemical composition of the drug in serum, both total and unbound, and drug and metabolites, both free and conjugated, in urine were determined by a combination of the direct and indirect chromatographic procedures to enantiomeric analysis. 3. The oral clearance of (S) -ibuprofen was significantly greater than that of the R -enantiomer (74.5 ± 18.1 versus 57.1 ± 11.7 ml?min -1 ; p < 0.05) and the clearance of (R) -ibuprofen via inversion was ca two fold that via alternative pathways. 4. Some 74.0 ± 9.6% of the dose was recovered in urine over 24 h as ibuprofen, 2-hydroxyibuprofen and carboxyibuprofen, both free and conjugated with glucuronic acid. Analysis of the stereochemical composition of the urinary excretion products indicated that 68% of the dose of (R) -ibuprofen had undergone chiral inversion. 5. Metabolism via glucuronidation and both routes of oxidation, showed enantio-selectivity for (S) -ibuprofen, the enantiomeric ratios (S/R) in partial metabolic clearance being 7.1, 4.8 and 3.4 for formation of ibuprofen glucuronide, 2-hydroxyibuprofen and carboxyibuprofen respectively. 6. Modest stereoselectivity was observed in the formation of (2' R, 2 R) - and (2' S, 2 S) -carboxyibuprofen in comparison to the alternative diastereoisomers, the ratios in formation clearance being 1.6 and 1.2 respectively.     

三氟柳胶囊在中国健康志愿者体内的药动学研究

目的研究中国健康志愿者单剂量和多剂量口服三氟柳胶囊的药动学特征,为中国人临床用药提供参考依据。方法健康志愿者40名,随机分为4组,每组10人,男女各半。单次给药的低、中、高3组给药剂量分别为300、600和900 mg;多次给药组每次给药600 mg,连续7 d。观察不良事件,HPLC法同时测定血浆中三氟柳及其活性代谢物4-三氟甲基水杨酸(2-hydroxy-4-trifluoromethyl benzoic acid,HTB)的质量浓度,计算药动学参数。结果 30名受试者分别单次口服三氟柳胶囊低、中、高3个剂量后,血浆中三氟柳ρmax分别为(5.3±2.2)、(6.4±2.1)和(11.4±2.9)mg·L-1,AUC0-t分别为(6.1±2.1)、(10.2±2.8)和(15.6±3.9)mg·h·L-1;活性代谢物HTB的ρmax分别为(40.6±7.0)、(66.7±10.5)和(103.6±8.6)mg·L-1,AUC0-t分别为(2 235.0±537.5)、(4 108.4±1 366.1)和(6 018.8±1 123.2)mg·h·L-1;连续给药600 mg后,三氟柳和活性代谢物HTB的ρav分别为(0.6±0.1)和(111.0±18.0)mg·L-1,AUCss分别为(15.5±3.2)和(2 664.4±432.6)mg·h·L-1,AUCss0-t分别为(14.7±2.6)和(8 545.3±1 815.4)mg·h·L-1;对各剂量组主要药动学参数性别间进行t检验,除900 mg组Vd性别差异外,其他参数均无显著性差异(P>0.05)。结论中国人群口服三氟柳胶囊后,药物和活性代谢物HTB在本研究剂量范围内呈线性动力学特征,主要药动学参数无性别差异;三氟柳在体内无蓄积,但其活性代谢物HTB却存在蓄积现象,临床用药时应注意给药时间间隔。     

奥拉西坦注射液在中国健康受试者体内的药动学

目的:研究奥拉西坦注射液在中国健康受试者体内的药动学特性.方法:采用开放随机交叉设计实验,用高效液相色谱法测定8名健康受试者分别单次静脉滴注2 g或4 g奥拉西坦后的血清中药物浓度,数据处理采用DAS软件处理.结果:奥拉西坦注射液主要药动学参数分别为Gmax(110.9±29.2)mg·L-1和(214.6±48.0)mg·L-1,AUC0-t(200.9±36.6)mg·h·L-1和(451.6±106.9)mg·h·L-1,t1/2β(3.0±0.6)h和(3.8±0.4)h,CL/F(10.2±2.0)mL·kg·h-1和(3.9±1.0)mL·kg·h-1,V/F(59.3±48.8)mL·kg-1和(31.6±18.3)mL·kg-1.结论:静脉滴注奥拉西坦2,4 g,耐受良好,实验中没有观察到不良反应.     

单次口服法罗培南钠片的人体药动学

目的：研究中国健康受试者单次口服不同剂量法罗培南钠片后的药动学。方法：30名健康受试者（男、女各15名）按性别随机分为3组（每组男女各5名），分别口服低、中、高（150，300，600mg）3个剂量的法罗培南钠片，于不同时间分别测定血浆中法罗培南浓度。结果：法罗培南的体内经时过程符合有滞后时间的一室模型，3个剂量组的tmax分别为（1．0&#177;0．5），（0．8&#177;0．5），（0．88&#177;0．27）h；Cmax分别为（2．2&#177;0．8），（4．8&#177;1．8），（9．7&#177;2．9）mg&#183;L^-1；AUC0-t分别为（4．1&#177;2．0），（7．8&#177;4．5），（18．7&#177;6．5）mg&#183;h&#183;L^-1；AUC0-∞分别为（4．2&#177;2．0），（7．8&#177;4．6），（18．9&#177;6．6）mg&#183;h&#183;L^-1；t1，2分别为（1．11&#177;0．28），（0．97&#177;0．21），（1．1&#177;0．4）h；CLz/F分别为（46．8&#177;27．5），（48．8&#177;21．4），（34．8&#177;9．9）L&#183;h^-1。结论：健康人单剂量口服法罗培南钠片的体内药动学符合有滞后时间的一房室模型。Cmax与AUC与服药剂量呈正相关，不同性别受试者单剂量口服法罗培南钠片后的药动学参数在性别受中无明显差异，单剂量口服法罗培南钠片在健康人体的代谢特征基本与文献报道参数一致．     

Population pharmacokinetics of fentanyl in healthy volunteers.

The authors compared the population pharmacokinetics of fentanyl using a standard individualized modeling (SIM) approach versus that of a nonparametric expectation maximization (NPEM) approach. The pharmacokinetic properties of fentanyl administered as a single 5 ug/kg intravenous infusion were evaluated in 18 healthy volunteers by use of SIM as well as with NPEM. NPEM-derived parameters were a total body clearance of 2.12 +/- 0.28 L/kg/h, distributional clearance of 8.43 +/- 4.58 L/kg/h, central volume of distribution of 1.22 +/- 0.21 L/kg, and peripheral volume of distribution of 1.81 +/- 1.47 L/kg. Identified parameter values from the modeling methods resulted in virtually identical simulated profiles; this finding was confirmed when median values noted were not statistically significantly different between modeling methods (SIM or NPEM). However, the NPEM algorithm uniquely identified a greater distributional clearance in the elderly population and also illustrated a profile with at least 10% of the study population having a very high clearance of fentanyl. This finding may affect the therapeutic use of fentanyl. NPEM allows for a more informative global representation of a drug's pharmacokinetics.     

Single-dose pharmacokinetics and safety of iptakalim hydrochloride in Chinese healthy volunteers

Objectives To investigate the safety, pharmacokinetics and food effect of iptakalim in healthy adult Han Chinese volunteers. Methods Study 1 was a randomized open‐label, Latin square designed, single‐dose, three‐period, self‐control crossover study. Six men and six women received 5, 10 and 20 mg of iptakalim orally. Study 2 was a randomized, open‐label, single‐dose, two‐period, self‐control crossover study. Ten men were included and each subject received 5 mg iptakalim orally, fasting and nonfasting. Key findings No adverse effects were reported and no clinically meaningful changes in vital signs were found. Cmax, AUC_0–t and AUC_0–∞ were proportional over the dose levels of 5, 10 and 20 mg. Tmax, t½ and CL/F were similarly independent of dose level. In the 5 mg and 20 mg group, the Cmax, AUC_0–t and AUC_0–∞ in women were significantly higher than in men, although they showed no difference after correction by mg/kg doses in the 5 mg group. At the 5‐mg dose level, no significant difference in pharmacokinetics was found in nonfasting and fasting subjects. Conclusions Single‐dose pharmacokinetics of iptakalim showed dose proportionality over the dose levels of 5–20 mg. The pharmacokinetics showed gender differences in the 5 and 20 mg groups. Food had almost no impact on the pharmacokinetics at the 5 mg level.