Pharmacokinetics and bioequivalence evaluation of 2 levosulpiride preparations after a single oral dose in healthy male Korean volunteers

OBJECTIVE: To evaluate the bioequivalence of a single oral 25 mg dose of 2 levosulpiride preparations in healthy male Korean volunteers. SUBJECTS, MATERIALS AND METHODS: The study was conducted as a randomized, 2-period crossover design in 28 healthy male Korean volunteers who received a single oral dose of 25 mg levosulpiride tablet in each study period. There was a 6-day washout period between the doses. Serum concentrations of levosulpiride up to 36 hours after the administration were determined using a validated HPLC method with fluorescence detection. In addition, in vitro dissolution profiles of both preparations were examined. The pharmacokinetic parameters such as AUC(0-t) (the area under the curve from zero to the time), AUC(0-infinity) (the area under the curve from zero to infinity), Cmax (maximum serum concentration), tmax (time to reach Cmax) and t1/2 (terminal half-life) were analyzed by non-compartmental analysis, and the analysis of variance (ANOVA) was carried out using logarithmically transformed AUC(0-t), AUC(0-infinity) and Cmax, and untransformed Tmax. RESULTS: In vitro dissolution profiles were similar by calculating similarity factor (f2 = 67.73). There were no significant differences between the 2 preparations in AUC(0-t), AUC(0-infinity) and Cmax. The point estimates (90% confidence intervals) for AUC(0-t), AUC(0-infinity) and Cmax were 1.085 (1.003-1.173), 1.069 (0.991-1.153) and 1.075 (0.954 to 1.210), respectively, satisfying the bioequivalence criteria of 0.80-1.25 as proposed by the US FDA and the Korean legislation. No statistically significant difference was found for tmax and t1/2 values. CONCLUSION: From the results of the present study, it is indicated that the 2 preparations of levosulpiride are bioequivalent and it can be assumed that they are therapeutically equivalent and exchangeable in clinical practice.     

中国汉族和朝鲜族健康志愿者单剂量口服氟康唑片的药物动力学考察

目的研究汉族和朝鲜族健康志愿者单剂量口服氟康唑片的药物动力学。方法健康汉族和朝鲜族受试者各10名,男女各半,口服氟康唑片200 mg,定时采血,用RP-HPLC法测定血药质量浓度,用drug and statistics(DAS 2.0.1)软件程序进行数据处理,用SPSS软件程序进行统计分析。结果汉族和朝鲜族受试者主要药物动力学参数ρmax为(4.91±0.67)、(4.70±0.86)mg.L-1;tmax为(1.90±0.90)、(2.55±1.07)h;t1/2为(33.07±5.90)、(31.02±6.02)h;AUC(0-96)为(189.61±32.91)、(183.75±31.83)mg.h.L-1,AUC(0-∞)为(219.21±40.46)、(209.93±46.37)mg.h.L-1。统计结果显示两民族受试者主要药物动力学参数差异无统计学意义。结论汉族、朝鲜族两民族的种族差异对氟康唑片的药物动力学无影响。     

单剂量口服酒石酸唑吡坦在中国朝鲜族和汉族健康人体内的药代动力学

目的 研究酒石酸唑吡坦(镇静催眠药)在中国朝鲜族和汉族健康受试者体内的药代动力学.方法 选择朝鲜族和汉族健康受试者各10名(5男、5女),每人口服酒石酸唑吡坦10 mg后,用高效液相色谱-荧光检测法测定受试者血浆中酒石酸唑吡坦的血药浓度,用DAS 2.0药代动力学软件进行数据处理.结果 朝鲜、汉两民族受试者口服酒石酸唑吡坦后主要药代动力学参数,t1/2分别为(2.04±0.47),(2.21±0.77) h,tmax分别为(0.98±0.22),(0.93±0.47)h,Cmas分别为(178.13±43.08),(190.81±70.59) μg·L-1,AUC0-12分别为(578.88±216.25),(624.48±192.15) μg·L-1·h,AUC0-∞分别为(597.48±227.97),(649.58±210.17) μg·L发-1·h.结论 服用酒石酸唑吡坦后,汉族,朝鲜族受试者各主要药代动力学参数之间无显著差异(P>0.05).     

单剂量口服非洛地平缓释片的药动学及生物等效性

目的研究单剂量口服国产非洛地平缓释片在健康志愿者体内的药动学特征,并评估其与参比制剂之间的生物等效性。方法 20名健康男性志愿者采用两制剂双周期交叉试验设计。以尼莫地平为内标,采用LC-MS/MS法测定血中药物浓度。以BAPP 2.2计算其药动学参数,评价受试制剂与参比制剂之间的生物等效性。结果 20名受试者单剂量口服10 mg受试制剂和参比制剂后非洛地平的主要药动学参数ρmax）分别为（3.09±1.03）μg·L^-1和（2.68±0.88）μg·L^-1;tmax分别为（3.8±1.0）h和（3.5±1.4）h;t1/2分别为（14.49±2.72）h和（13.74±3.42）h;MRT为（19.87±2.62）h和（19.08±4.73）h;AUC0→48为（30.83±6.04）μg·h·L^-1和（31.42±5.78）μg·h·L^-1;AUG0→∞为（34.00±5.76）μg·h·L^-1和（34.93±6.54）μg·h·L^-1。受试制剂与参比制剂的主要药动学参数经统计学分析无明显差异。受试制剂的相对生物利用度为（98.5±11.0）%。结论国产非洛地平缓释片与其参比制剂之间具有生物等效性。     

单次口服莫达芬尼片在中国健康志愿者的药代动力学

目的研究单次口服莫达芬尼片的药代动力学。方法选择9名健康成年男性受试者分别单次口服100,200,300mg 3个剂量的莫达芬尼片后,用HPLC法测定血中原形药莫达芬尼及代谢产物莫达芬尼酸浓度,用3P97软件进行数据处理,计算药代动力学参数。结果原形药莫达芬尼的药-时曲线符合二房室模型,其主要药代动力学参数的Cmax、AUC0-∞、AUC0-t随剂量加大而增加;t1/2b、tmax、b、CL与给药剂量无关。莫达芬尼片原形药经肾排泄较少,48h经肾累积排泄率分别为(4.44±4.28)%,(3.35±2.20)%和(2.86±1.39)%。主要代谢产物莫达芬尼酸药-时曲线符合二房室模型,48h莫达芬尼酸经肾累积排泄率分别为(33.51±18.90)%,(32.36±19.92)%和(22.88±6.89)%。结论莫达芬尼在100～300mg内,呈线性动力学特征而无饱和性,其消除过程是经肝脏代谢,代谢产物为莫达芬尼酸,代谢产物主要经肾排泄。     

单次口服阿奇霉素片在中国健康志愿者的药代动力学

目的研究阿奇霉素(大环内酯类抗生素)在中国健康人体的药代动力学。方法 10名健康志愿者单剂量口服阿奇霉素500 mg后,高效液相色谱-紫外检测法测定血清药物浓度;用AIC法结合F检验判别房室模型, DAS程序计算药代动力学参数。结果主要的药代动力学参数:Ka为(0．87 ±0．27)h-1,t1／2β为(39．66±10．85)h,tmax为(2．60±0．52)h,Cmax为(451．19 ±67．72)μg·L-1,CL／F为(0．56±0．13)L·(h·kg)-1,AUC0-144和 AUC0-∞分别为(13．68±2．92)mg·h·L-1和(13．71±2．91)mg·h·L-1。结论最佳房室模型为二室模型。     

Bioequivalence of two aceclofenac tablet formulations after a single oral dose to healthy male Korean volunteers

A bioequivalence study of aceclofenac tablets (test formulation: Dong-A, reference formulation: Airtal) was conducted in 16 healthy male Korean volunteers who received each medicine at a dose of 100 mg in a 2 x 2 crossover study. There was a one-week washout period between the doses. Plasma concentrations of aceclofenac were monitored by high-performance liquid chromatography over a period of 24 hours after the administration. AUCinf (the area under the plasma concentration-time curve from time zero to time infinity) was calculated by the linear-log trapezoidal method. Cmax (maximum plasma drug concentration) and tmax (time to reach Cmax) were compiled from the plasma concentration-time data. Analysis of variance was carried out using logarithmically transformed AUCinf and Cmax, and non-transformed tmax. There were no significant differences between the medications in AUCinf and Cmax. The point estimates and 90% confidence intervals for AUCinf (parametric) and Cmax (parametric) were 1.04 (0.93 to approximately 1.17) and 0.99 (0.91 to approximately 1.08), respectively, satisfying the bioequivalence criteria of the European Committee for Proprietary Medicinal Products and the US Food and Drug Administration Guidelines. The corresponding value for tmax was 0.75 (0.00 to approximately 1.00). Moreover, the modified Pitman-Morgan's adjusted F-test indicated that the bioavailabilities of aceclofenac in the 2 medications were comparable regarding intra- and interindividual variability. Therefore, these results indicate that the 2 medications of aceclofenac are bioequivalent and, thus, may be prescribed interchangeably.     

朝鲜族和汉族健康受试者单剂量口服盐酸曲马多的药物动力学

目的研究盐酸曲马多在中国朝鲜族和汉族健康受试者体内的药物动力学。方法朝鲜族和汉族健康受试者各10名,单剂量口服盐酸曲马多胶囊100 mg,用高效液相色谱荧光检测法测定受试者血浆中盐酸曲马多的血药浓度,研究其药物动力学,用DAS Ver 2.0药物动力学软件进行数据处理。结果汉族和朝鲜族健康受试者口服盐酸曲马多后的药-时曲线均符合一室开放模型,主要药物动力学参数分别为t1/2(6.2±1.0)h和(6.4±1.6)h,tmax(2.4±0.7)h和(2.0±0.9)h,ρmax(401.4±78)μg.L-1和(418.9±48)μg.L-1,AUC0-36(4297.1±1261.8)μg.h.L-1和(4071.8±1387.3)μg.h.L-1,AUC0-∞(4456.1±1318.5)μg.h.L-1和(4255.1±1548.2)μg.h.L-1。结论服用盐酸曲马多后,汉族和朝鲜族健康受试者的ρmax、AUC0-t、AUC0-∞个体间差异较大,但2组受试者之间药物动力学参数的差异无统计学意义(P>0.05)。     

Pharmacokinetics and metabolic disposition of sirolimus in healthy male volunteers after a single oral dose

The pharmacokinetics and metabolic disposition of sirolimus (rapamycin, Rapamune), a macrocyclic immunosuppressive agent for the prevention of allograft rejection in organ transplantation, were investigated in 6 healthy male volunteers after a single nominal 40-mg oral dose of the C-radiolabeled drug, with the added aim of assessing the potential role of sirolimus metabolites in the clinical pharmacology of the parent drug. The absorption of parent drug and derived materials was rapid (tmax 1.3 +/- 0.5 hours, mean +/- SD), and the elimination of sirolimus was slow (t(1/2) 60 +/- 10 hours, mean +/- SD) in whole blood. The high whole blood to plasma (B/P) concentration ratio of sirolimus (142 +/- 39) was consistent with its extensive partitioning into formed blood elements. The markedly lower B/P value based on radioactivity (2.7 +/- 0.4) suggested that drug-derived products partitioned into formed blood elements to a much lesser extent. Based on AUC0-144h values, unchanged sirolimus represented an average 35% of total radioactivity in whole blood. Drug-derived products in whole blood were characterized by HPLC, LC/MS, and LC/MS/MS as 41-O-demethyl, 7-O-demethyl, and several hydroxy, dihydroxy, hydroxy-demethyl and didemethyl sirolimus metabolites. The percentage distribution of sirolimus metabolites in whole blood ranged from 3%-10% at 1 hour to 6%-17% at 24 hours after drug administration. Based on their low immunosuppressive activities and relative abundance in whole blood of humans after sirolimus administration, metabolites of sirolimus do not appear to play a major role in the clinical pharmacology of the parent drug. A majority of the administered radioactivity (91.0 +/- 8.0%) was recovered from feces, and only 2.2% +/- 0.9% was renally excreted.     

Randomised crossover studies of the bioequivalence of two fenofibrate formulations after administration of a single oral dose in healthy volunteers

Bioequivalence of a newly developed semi-solid formulation (Lidose) of fenofibrate (CAS 49562-28-9), and a reference, micronized formulation of fenofibrate was investigated in two randomised, open-label clinical studies with a crossover design. Both studies involved two distinct groups of 24 healthy volunteers. Doses of 67 mg and 200 mg, respectively, were used in study 1 and study 2. On day 1, a single oral dose was administered to all subjects, using one of the two formulations to be compared. Single oral dosing with the other formulation occurred after a washout period of at least 8 days. Blood samples were taken after each dosing for measurement of plasma fenofibric acid concentrations by high-performance liquid chromatography (HPLC) combined with fluorescence detection, and plasma pharmacokinetic parameters were determined. No statistically significant differences were noted for Cmax, Tmax, AUC0-t and AUC0-variation of between subjects treated with the new formulation and those receiving the reference formulation. Side effects were mild and not significantly different between the two fenofibrate preparations. These two studies based on validated methods demonstrate that the new and the reference fenofibrate formulations are bioequivalent when administered at the two doses studied.     

单次口服瑞舒伐他汀钙片在中国健康志愿者的药代动力学

目的研究瑞舒伐他汀钙片(降血脂药)在中国健康志愿者体内单次给药的药代动力学特征。方法选择健康受试者12例,按3×3拉丁方设计,分别单次给与瑞舒伐他汀钙片5,10和20mg后,采用LC-MS测定不同时间血中瑞舒伐他汀的浓度,以BAPP软件进行数据处理,求算药代动力学参数。结果3个不同剂量组瑞舒伐他汀的主要药代动力学参数:Cmax分别为(6.54±2.06),(10.61±3.35),(22.85±7.32)ng.mL-1;AUC0-72分别为(77.83±25.43),(136.12±48.63),(275.98±81.98)h.ng.mL-1;tmax分别为(3.7±1.2),(3.8±0.8),(3.4±1.0)h;t1/2分别为(23.26±5.54),(25.64±14.02),(20.54±5.80)h;CL/F分别为(65.40±19.05),(76.96±36.47),(76.18±33.35)L.h-1;各剂量组的Cmax、AUC0-72、AUC0-∞随剂量的增加而成比例的增大,各组的Ka、Ke、tmax、t1/2ka、t1/2、MRT、CL/F等差异无统计意义。结论口服给药剂量为5～20mg时,瑞舒伐他汀钙在国人体内具有线性药代动力学特征。     

单剂量巴洛沙星片在健康人体的药代动力学

目的 研究巴洛沙星片(喹诺酮类抗生素)在健康志愿者体内的药代动力学.方法 采用随机开放的三周期交叉试验设计,健康志愿者12例随机分成3组,分别单剂量交叉口服巴洛沙星100、200、400 mg,以反相高效液相色谱法测定给药后不同时间点巴洛沙星的血浆浓度,血药浓度经DAS软件处理.结果 巴洛沙星的主要药代动力学参数Cmax分别为(0.93±0.30)、(1.97±0.60)、(3.54±0.83)mg·L-1,t1/2分别为(8.78±2.65)、(8.11±1.42)、(7.68±1.31)h,AUC0～t分别为(9.9±1.4)、(20.38±3.20)、(40.02±5.54)mg·h·L-1,AUC0-∞分别为(10.41±1.44)、(21.19±3.16)、(44.07±7.29)mg·h·L-1.结论 单剂量口服巴洛沙星片,其消除半衰期t1/2与给药剂量无关;而Cmax、AUC0-t、AUC0～∞与剂量呈明显相关性,且随给药剂量的增大而增加.表明巴洛沙星在体内为线性动力学特征.     

三种尼扎替丁制剂在中国健康人体的药动学及生物等效性

目的：评价健康受试者单剂量口服受试尼扎替丁片剂、胶囊以及参比尼扎替丁片剂的人体药动学与生物等效性。方法：采用3种制剂3周期随机交叉试验设计，HPLC法测定18例男性健康受试者单剂量口服150mg受试尼扎替丁片剂、胶囊和参比尼扎替丁片后的血药浓度；采用非室模型计算药动学参数；AUC，Cmax经对数转换后进行方差分析并计算90％置信区间。结果：受试尼扎替丁片剂、胶囊和参比尼扎替丁片剂的Cmax分别为（1280±359），（1377±438）和（1140±269）ng·mL^-1；tmax分别为（0．986±0．358），（1．069±O．362）和（1．125±O．464）h；tl/2分别为（1，556±O．312），（1．441±O．309）和（1．51l±O．259）h：AUC 0-t分别为（3864．50±662．77），（3775．06±596．18）和（3685．83±561．46）ng·h·mL^-1；AUC0-∞分别为（3896．55±668．89），（3798．17±605．86）和（3711．37±563．63）ng·h·mL^-1。结论：受试制剂尼扎替丁片、胶囊与参比尼扎替丁片具有生物等效性。     

三种替米沙坦制剂在中国健康人体的药动学及生物等效性

目的:评价健康受试者单剂量口服受试替米沙坦胶囊,片剂以及参比替米沙坦片剂的人体药动学与生物等效性。方法:采用3种制剂3周期随机交叉试验设计,LC-MS-MS法测定18例男性健康受试者单剂量口服80 mg国产替米沙坦胶囊、替米沙坦片和进口替米沙坦片后替米沙坦的血药浓度。采用非室模型计算药动学参数。AUC,Cmax对数转换后进行方差分析并计算90％置信区间。结果:国产替米沙坦胶囊、替米沙坦片剂,进口替米沙坦片剂的主要药动学参数分别为:Cmax=(1 016．3±571．7),(869．7±623．8)和(905．7±583．4)ng·mL-1, Tmax=(1．5±1．0),(1．5±0．6)和(1．6±1．1)h,AUC0-t=(7 372±3 955),(7 373±4 347)和(6 774±3 758)ng·h·mL-1,AUC0-∞=(8 432±4 946),(8 623±5 687)和(7 502±4 663)ng·h·mL-1,t1/2=(24．9±9．2),(24．5±11．9)和(23．0±6．5)h。结论:国产替米沙坦胶囊、替米沙坦片与进口替米沙坦片具有生物等效性。     

单剂量静脉滴注兰索拉唑在中国健康人体的药代动力学

目的 研究中国健康志愿者单次静脉滴注兰索拉唑(抑胃酸药)的药代动力学特点.方法 12名健康志愿者,先后单次静滴3个剂量(15,30,60 mg)兰索拉唑;用高效液相色谱-紫外检测法测定给药后不同时间点的血药浓度,用3P97软件计算药代动力学参数.结果 血药浓度-时间曲线符合二房室模型,健康受试者单次静滴3个剂量(15,30,60 mg)兰索拉唑后主要的药代动力学参数:C_(max)分别为(1105.65±506.24),(2171.33±799.02),(4070.53±643.04)μg·L~(-1);t_(1/2)分别为(1.63±0.86),(2.30±2.01),(1.90±1.19)h;AUC_(0-12)分别为(991.16±814.49),(3495.87±1770.92),(8351.14±2599.90)μg·h·L~(-1).结论 兰索拉唑的体内过程在男女性别间无显著差异,剂量在15～60 mg内较安全.     

单剂量静脉滴注硫酸头孢噻利在中国健康志愿者的药代动力学

目的 研究单剂鼍静脉滴注硫酸头孢噻利(第4代头孢类抗生素)注射液在中国健康志愿者的药代动力学.方法 10名健康志愿者,随机分为2组,分别单剂量静脉滴注硫酸头孢噻利1、2 g;用高效液相色谱法测定给药后不同时间点的血药浓度和尿药浓度,用DAS Ver 2.0软件计算药代动力学参数.结果 单剂量静脉滴注硫酸头孢噻利1、2 g后,其药代动力学参数:t1/2分别为(2.58±0.40)、(2.51±0.23)h;tmax分别为(0.97±0.08)、(0.94±0.11)h;Cmax分别为(56.20±8.68)、(107.80±18.30)μg·mL-1;AUC0～t分别为(154.00±25.30)、(303.50±58.20)μg·mL-1;24 h尿药累积排泄率分别为(81.20±10.10)%、(83.00±3.39)%.结论 本法专属性强、灵敏度高、操作简便,适用于头孢噻利的药代动力学研究.硫酸头孢噻利在人体内呈线性药代动力学过程.     

单次静滴D-聚甘酯注射液在中国男性健康志愿者的药代动力学

目的 研究中国健康男性志愿者单次静滴D-聚甘酯注射液（抗拴塞药）的药代动力学。方法 选27名健康男性志愿者，随机分成3组，分别接受单次静滴D-聚甘酯注射液100，200，300mg。用免疫荧光比浊法测定给药后不同时间点血浆的部分凝血活酶时间（aPTT），计算相应的血药浓度，用3P97软件计算药代动力学参数。结果血药浓度-时间曲线符合二房室模型，3组的药代动力学参数β、t1/2β、CL无显著性差异，与给药剂量无关，3组AUC0-39h随给药剂量的加大而增加；但300mg组AUC0-39/dose和C0／dose与另2组差异有统计学意义。结论 在100-200mg内，D-聚甘酯注射液的体内过程，基本符合线性动力学特征。     

单剂量口服匹伐他汀钙片在中国健康志愿者的药代动力学和安全性

目的 研究国产匹伐他汀钙片(降血脂药)在中国健康志愿者体内单次给药的药代动力学特征及安全性.方法 选择中国健康受试者12例,按3×3拉丁方设计,分别单次给予匹伐他汀钙片1,2,4 mg后,采用液相色谱-串联质谱联用法测定不同时间血中匹伐他汀的浓度,以DAS 2.0软件进行数据处理,求算药代动力学参数.结果 3个不同剂量组匹伐他汀的主要药代动力学参数:t_(1/2β)分别为(11.39±7.66),(10.00±7.30),(11.30±7.95)h;t_(max)分别为(0.83±0.29),(0.73±0.20),(0.85±0.46)h;C_(max)分别为(30.48±11.66),(60.80±22.97),(120.98±35.51)ng·mL~(-1);AUC_(0→72h)分别为(93.19±26.61),(179.46±52.86),(364.37±94.74)ng·mL~(-1)·h;AUC_(0→∞)分别为(96.70±27.42),(183.34±53.62),(372.86±95.84)ng·mL~(-1)·h;各剂量组的C_(max)、AuC_(0-72h)、AUC_(0→∞)随剂量的增加而成比例的增大,各组的K_(10)、t_(max)、t_(1/2β)、MRT_(0-72)、MRT_(0→∞)、CL/F、V/F等差异无统计意义.结论 口服给药剂量为1～4 mg时,匹伐他汀钙片在中国健康人体内具有线性药代动力学特征,其代谢特征基本与文献报道一致.     

Pharmacokinetics of nilvadipine after single oral doses in healthy volunteers

Forty healthy male Caucasian volunteers were randomly assigned to five treatment groups to receive a placebo or a 4, 8, 12, 16 or 20 mg dose of nilvadipine. The drug was well tolerated by the subjects at all dose levels. Pharmacokinetic parameters for nilvadipine were determined using model-independent methods. There were no significant differences (p greater than 0.05) in the time to the maximum plasma concentration (Cmax) (tmax), the elimination half-life or the mean residence time among the five treatment groups. Up to doses of about 12 mg, there was a linear relationship between dose and Cmax or area under the plasma concentration-time curve (AUCO----infinity). At doses of 16 and 20 mg, the relationship between dose and Cmax or AUCO----infinity was no longer linear, suggesting that the pharmacokinetics of the drug after single oral doses greater than about 12 mg may be dose-dependent, probably due to concentration-dependent first-pass hepatic elimination of the drug.