Pharmacokinetics of pantoprazole following single intravenous and oral administration to healthy male subjects

Summary The plasma pharmacokinetics of pantoprazole have been investigated following single intravenous infusion and single oral administration at a dose of 40 mg to 12 healthy male subjects in a randomised cross-over study. Both treatments were generally well tolerated and no relevant compound-related adverse events were noted. The plasma pharmacokinetics of pantoprazole following intravenous infusion in this group of subjects were characterised by a total plasma clearance of 0.13 l·h⁻¹·kg⁻¹ and apparent terminal elimination half-life 1.9 h. The apparent volume of distribution estimated at steady state (0.171·kg⁻¹) was compatible with the localization of a major fraction of the compound in extracellular water. Following oral administration as an enteric-coated tablet formulation, a variable onset of absorption was followed by rapid attainment of maximum plasma concentrations of pantoprazole. Pantoprazole was well absorbed following oral administration; the absolute systemic bioavailability of the compound was estimated as 77% (95% CI, 67 to 89%).     

单剂量口服他达拉非在中国健康男性受试者的药代动力学和安全性

目的 研究中国健康男性受试者单剂量口服他达拉非的药代动力学和安 全性。方法 用双盲随机安慰剂对照三交叉设计。在3个周期随机单次服用 他达拉非10,20 mg或安慰剂,采集静脉血,用液相色谱-质谱法测定血药浓度 并计算药代动力学参数。结果 单次服用他达拉非10,20 mg后的主要药代动 力学参数AUC0-t分别为3750和7180 ng·h·mL-1;AUC0-∞分别为3820和 7370 ng·h·mL-1;Cmax分别为172和274 ng·mL-1;tmax分别为3．00和4．00 h;CL／F分别为2．61和2．71 L·h-1;V／F分别为67．6和73．2 L。结论 他达 拉菲在10-20 mg,中国健康男性受试者较安全,且AUC与剂量呈正相关。     

Pharmacokinetics of antofloxacin hydrochloride in healthy male subjects after multiple intravenous dose administration

The purpose of the study was to evaluate pharmacokinetic characteristics of antofloxacin hydrochloride, a new fluoroquinolone antibiotic, during a multiple, intravenous dosing regimen. Twelve healthy, Chinese male volunteer subjects were each given 300?mg of antofloxacin by intravenous infusion once daily for 7 days. Blood and urine samples were taken at designated time points for analysis of antofloxacin concentration by high-performance liquid chromatography (HPLC). Safety and tolerability were assessed by evaluation of subject complaints, vital signs, electrocardiograms, electroencephalograms, clinical chemistry parameters, haematology and urinalysis and prothrombin time. The serum steady concentration of antofloxacin was obtained in 96?h after the administration of a daily intravenous dose of 300?mg of the drug. In the present study, the following pharmacokinetic parameters after 7 days of treatment with antofloxacin were determined to be: C(max) 3.81?±?0.66?mg/L, C(min) 0.85?±?0.19?mg/L, AUC(0-24) 60.51?±?8.30?mg/L·h, C(av) 2.52?±?0.35?mg/L, PTF 87.45?±?3.37%, t(1/2)β 20.34?±?1.88?h. The C(max) and AUC(0-24) after 7-day treatment were both higher than after the first dose (by 43% and 110%, respectively). The cumulative urinary elimination of antofloxacin within 96?h after the last dose was about 56%. During the study, there were neither subject complaints nor significant adverse clinical findings. Antofloxacin, administered intravenously as a single, daily 300?mg dose for 7 days, demonstrated favourable pharmacokinetic characteristics and tolerability. The results of this study indicate that antofloxacin hydrochloride is suitable for further clinical study.     

Pharmacokinetics of antofloxacin hydrochloride in healthy male subjects after multiple intravenous dose administration

1. The purpose of the study was to evaluate pharmacokinetic characteristics of antofloxacin hydrochloride, a new fluoroquinolone antibiotic, during a multiple, intravenous dosing regimen.

2. Twelve healthy, Chinese male volunteer subjects were each given 300?mg of antofloxacin by intravenous infusion once daily for 7 days. Blood and urine samples were taken at designated time points for analysis of antofloxacin concentration by high-performance liquid chromatography (HPLC). Safety and tolerability were assessed by evaluation of subject complaints, vital signs, electrocardiograms, electroencephalograms, clinical chemistry parameters, haematology and urinalysis and prothrombin time.

3. The serum steady concentration of antofloxacin was obtained in 96?h after the administration of a daily intravenous dose of 300?mg of the drug. In the present study, the following pharmacokinetic parameters after 7 days of treatment with antofloxacin were determined to be: C_max 3.81?±?0.66?mg/L, C_min 0.85?±?0.19?mg/L, AUC_0–24 60.51?±?8.30?mg/L·h, C_av 2.52?±?0.35?mg/L, PTF 87.45?±?3.37%, t_1/2β 20.34?±?1.88?h. The C_max and AUC_0–24 after 7-day treatment were both higher than after the first dose (by 43% and 110%, respectively). The cumulative urinary elimination of antofloxacin within 96?h after the last dose was about 56%.

4. During the study, there were neither subject complaints nor significant adverse clinical findings.

5. Antofloxacin, administered intravenously as a single, daily 300?mg dose for 7 days, demonstrated favourable pharmacokinetic characteristics and tolerability. The results of this study indicate that antofloxacin hydrochloride is suitable for further clinical study.

     

Pharmacokinetics of ketotifen after oral administration to healthy male subjects.

The pharmacokinetics of 2 mg ketotifen from four different oral dosage forms were examined in two randomized, balanced cross-over studies. Forty healthy male subjects participated. Each of 20 subjects received two capsule formulations and each of the other 20 subjects received two syrup formulations. Ketotifen concentrations in plasma were determined by a modified GC-MS method. The limit of quantitation was 40 pg ml-1. Inter-day precision and accuracy calculated from quality control samples were 16.3 per cent (-1.9 per cent), 19.8 per cent (+4.5 per cent) and 23.6 per cent (+5.9 per cent) at plasma concentration levels of 86 (n = 18), 215 (n = 19) and 343 (n = 18) pg ml-1, respectively. Ketotifen was rapidly absorbed from all dosage forms reaching Cmax in the order of 400 pg ml-1 after the syrup formulations and 300 pg ml-1 after the capsule formulations within 2 to 4 h. The syrup formulations showed a significantly more rapid rate of absorption as assessed by Tmax. No significant differences in extent of absorption between dosage forms were observed. The terminal elimination half-life of ketotifen varied between subjects from 7 to 27 hours with a mean of about 12 h. The minor pharmacokinetic difference between dosage forms observed in this study is unlikely to be of clinical significance.     

Pharmacokinetics of rabeprazole following single intravenous and oral administration to healthy subjects

The study was designed to determine the absolute bioavailability of 20 mg rabeprazole tablets in normal, healthy subjects in comparison with intravenous administration of 20 mg rabeprazole. Twenty-eight healthy subjects were enrolled in this study. The study was a randomized, balanced, open-label, 2-period crossover study. Each subject was randomized at the beginning of the study to receive either a single 20 mg dose of rabeprazole intravenously or orally during Period 1. Following a 7-day washout period, all subjects received the alternate formulation during Period 2. Intravenous dose was given in constant infusion over five minutes. The absolute bioavailability of rabeprazole was 51.8%. The elimination half-life of rabeprazole sodium (1.47 +/- 0.82 h) after oral administration was significantly longer than the elimination half-life after intravenous administration (1.02 +/- 0.63 h), probably due to slower rate of absorption than that of elimination. The mean total body clearance was 283 +/- 98 ml/minutes following a 20 mg intravenous dose. The administration of rabeprazole sodium was safe as evidenced by the lack of serious adverse events and the rapid resolution of the mostly mild adverse events that occurred during the study. Both treatments were well-tolerated throughout the study. Rabeprazole was well-absorbed after oral administration.     

Pharmacokinetics of esomeprazole after oral and intravenous administration of single and repeated doses to healthy subjects

OBJECTIVE: To study the pharmacokinetics of esomeprazole, one of the optical isomers of omeprazole, after 20 mg or 40 mg single and repeated oral and intravenous administration to healthy subjects. The main metabolites of esomeprazole were also assessed after the 40-mg oral dose. METHODS: In two separate studies, 16 healthy male subjects and 16 healthy male and female subjects received intravenous doses of 20 mg and 40 mg esomeprazole, respectively, on the first investigation day. After a washout period of 5-14 days, the same doses (20 mg as a solution and 40 mg as a capsule) were given orally for 5 days and then again intravenously on day 6. Blood samples for determination of esomeprazole and its metabolites were collected 12 h or 24 h post-dose and were analysed using normal-phase liquid chromatography with ultraviolet (UV) detection. Pharmacokinetic parameters of esomeprazole and its metabolites were estimated using non-compartmental analysis. Geometric means and ratios of the geometric means together with 95% confidence intervals (CI) of the pharmacokinetic parameters were calculated using analysis of variance (ANOVA). RESULTS: Plasma clearance (CL) of esomeprazole decreased from 22 l/h to 16 l/h and from 17 l/h to 9 l/h following repeated dosing of 20 mg and 40 mg, respectively. Total area under the plasma concentration-time curve (AUC) increased (from 1.34 micromol x h/l to 2.55 micromol x h/l) with absolute bioavailability (F) being 50% on day 1 and 68% on day 5 after the 20-mg oral dose. AUC increased (from 4.32 micromol x h/l to 11.21 micromol x h/l) with F being 64% on day 1 and 89% on day 5 after the 40-mg oral dose. The plasma levels for esomeprazole sulphone were substantially higher on day 5 than on day 1, while those for 5-hydroxy esomeprazole were marginally higher on day 5 than on day 1 following repeated oral dosing of 40 mg esomeprazole. No side effects attributable to esomeprazole were noticed. CONCLUSION: The increased AUC of esomeprazole with repeated dosing is probably due to a combination of a decreased first-pass elimination and a decreased systemic clearance.     

口服后莫达非尼及其代谢产物在汉族健康人体内的药物动力学

目的研究莫达非尼及其代谢产物(莫达非尼酸)在中国汉族健康人体内的药物动力学过程。方法10名健康志愿者口服莫达非尼片200 mg,采用HPLC法测定给药后不同时间点的莫达非尼及其代谢物的浓度,用DSA软件求算其药物动力学参数,并比较药物动力学参数在性别上的差异。结果莫达非尼及其代谢物莫达非尼酸的药物动力学过程符合二室模型拟合,其药物动力学参数分别为:莫达非尼tmax(1.69±0.70)h,ρmax(4.14±1.21)mg.L-1,AUC0-∞(65.96±11.69)mg.h.L-1;莫达非尼酸tmax(3.06±0.94)h,ρmax(3.19±0.95)mg.L-1,AUC0-∞(45.94±13.44)mg.h.L-1。结论口服莫达非尼在人体内其原形及代谢产物药物动力学均符合二室模型拟合,其药物动力学参数没有性别差异。     

Pharmacokinetics of eltoprazine in healthy subjects

The pharmacokinetics of eltoprazine in healthy male subjects was investigated after intravenous and oral dosing in one study, and after oral dosing of 14C-eltoprazine in a second study. It was shown that the absorption of eltoprazine from the gastro-intestinal tract was complete, and that absolute bioavailability was 100%. The mean elimination half-life of eltoprazine in plasma was about 8 hours. Approximately 40% of the dose was excreted unchanged in urine.     

Pharmacokinetics and bioavailability of omeprazole after single and repeated oral administration in healthy subjects.

1. Ten healthy subjects were given 20 mg omeprazole EC (enteric coated) granules once daily for 8 days. An i.v. tracer dose of [14C]-omeprazole was given simultaneously with the first and last oral doses and blood sampling was performed thereafter. In order to study the extent of absorption at minimal acid exposure, a single dose of 20 mg omeprazole was also given as a buffered solution, before and after the treatment with EC granules. 2. Kinetic parameters of omeprazole after the i.v. tracer dose were unchanged on repeated dosing while AUC increased by approximately 40% for the solution and 60% for the EC granules. 3. The increased AUC is caused by an increased systemic availability, which may be explained by a decreased first-pass elimination during repeated treatment and/or by a reduced degradation of omeprazole in the stomach secondary to the profound decrease in intragastric acidity caused by the drug. 4. The implication of these findings is that the antisecretory effect of therapeutic doses of omeprazole must be studied during repeated administration and not judged from studies using single doses only.     

单剂量口服奥扎格雷钠在健康人体的药代动力学

目的研究健康人体单剂口服奥扎格雷钠口服液的人体药代动力学。方法12名健康志愿者口服奥扎格雷钠口服液200mg,用反相高效液相色谱法—二极管阵列紫外法测定血浆中奥扎格雷钠浓度,并求算其药代动力学参数。结果奥扎格雷钠口服液的药代动力学参数tmax为(0.42±0.12)h、Cmax为(3.10±1.06)mg·L-1、AUC0-t为(3.50±0.91)mg·h·L-1,t1/2β为(0.72±0.26)h。结论单剂量口服奥扎格雷钠,在体内分布及消除较快,且Cmax及AUC与剂量成正比。     

中国健康受试者单剂量静脉注射比阿培南的药代动力学

目的 研究中国健康受试者单剂量静脉注射比阿培南(碳青霉烯类抗生素)的药代动力学及安全性.方法 10名健康受试者分别静脉注射比阿培南300,600 mg 1 h,于1周后交叉注射另一剂量,用高效液相色谱-紫外法测定血浆和尿液中比阿培南的浓度,用WinNonLin计算其主要药代动力学参数.结果 10名受试者分别单剂量使用比阿培南300和600 mg后,比阿培南主要药代动力学参数:C_(max)分别为(11.33±2.71)和(26.80±5.11)μg·mL~(-1);AUC_(0-tn)分别为(18.01±4.66)和(42.78±-8.81)μg·mL~(-1)·h.结论 中国健康受试者单剂量使用比阿培南后,在300～600 mg内的体内过程呈线性药代动力学特征.     

Pharmacokinetics of ipratropium bromide after single dose inhalation and oral and intravenous administration

Single doses of ipratropium bromide were administered intravenously, orally and by slow inhalation to ten healthy male volunteers. The plasma level after oral administration followed a low but broad plateau persisting for several hours. After i.v. administration the kinetic parameters were: Vc = 25.9 l, V alpha = 13.1 l, V beta = 3.38 l, t1/2 alpha = 3.85 min, t1/2 beta = 98.4 min, AUC = 15.0 h.ng/ml, kel = 11.8 l/h and total clearance is 2325 ml/min. The bioavailability was 3.3% (range 0.9-6.1%) on comparing the plasma AUCs following i.v. and 20 mg oral administration. The cumulative renal excretion (0-24 h) after i.v. administration was compared with that after oral administration and inhalation. Following oral administration, the apparent systemic availability was around 2%, and after inhalation it was 6.9%. In comparison with oral placebo administration, only after i.v. administration was there a significant change in heart rate (from 63.7 to 90.2 beats/min). The systolic blood pressure rose from 115.1 to 119.6 mm Hg and the diastolic blood pressure from 68.3 to 78.3 mm Hg.     

Pharmacokinetics of sarizotan after oral administration of single and repeat doses in healthy subjects

OBJECTIVE: Sarizotan is a 5-HTIA receptor agonist with high affinity for D3 and D4 receptors. Here we report the pharmacokinetic and tolerability results from four Phase 1 studies. MATERIALS: Two single-dose (5 -25 mg, n = 25, 0.5 - 5 mg, n = 16) and two multiple-dose (10 and 20 mg b.i.d., n = 30, 5 mg b.i.d., n = 12) studies with orally administered sarizotan HCl were carried out in healthy subjects. METHODS: Plasma sarizotan HCl concentrations were measured using a validated HPLC method and fluorescence or MS/MS detection. Pharmacokinetic parameters were obtained using standard non-compartmental methods. RESULTS: Sarizotan was rapidly absorbed, group-median times to reach maximum concentration (tmax) ranged from 0.5 -2.25 h after single doses and during steady state. Maximum plasma concentration (Cmax) and tmax were slightly dependent on formulation and food intake, whereas area under the curve (AUC) was unaffected by these factors. AUC and Cmax increased dose-proportionally over the tested dose range. Independently of dose and time, sarizotan HCl plasma concentrations declined polyexponentially with a terminal elimination half-life (t1/2) of 5 - 7 h. Accumulation factors corresponded to t1/2 values, and steady state was reached within 24 h. Plasma metabolite concentrations were considerably lower than those of the parent drug. The ratio metabolite AUC : parent drug AUC was time- and dose-independent for all three metabolites suggesting that the metabolism of sarizotan is non-saturable in the tested dose range. CONCLUSIONS: The pharmacokinetics of sarizotan were dose-proportional and time-independent for the dose range 0.5 -25 mg). The drug was well-tolerated by healthy subjects up to a single dose of 20 mg.     

健康男性多次口服爱地那非片的药代动力学和安全性

目的 研究中国男性健康受试者多次口服枸橼酸爱地那非片(治疗阴茎勃起功能障碍)的安全性和药代动力学.方法 27名受试者随机分为30、45和60 mg 3个剂量组,每组9人,试验期间严密观察临床症状体征和不良事件,用LC-MS/MS测定多次服药后血浆中的药物浓度,并计算药代动力学参数.结果 受试者多次口服枸橼酸爱地那非片30、45和60 mg后,其主要药代动力学参数:Cmax分别为(256.6±106.6)、(435.7±115.4)和(918.6±442.5)ng·mL-1;Cav分别为(57.2±26.1)、(95.0±28.9)和(247.6±137.0)ng·mL-1;tmax分别为(1.1±0.6)、(1.2±0.6)和(1.6±0.5)h;t1/2分别为(4.5±0.3)、(4.4±0.6)和(3.9±0.6)h;AUC0-24h分别为(1373.3±625.6)、(2280.1±693.6)和(5941.8±3288.4)ng·h·mL-1;AUC0-36h分别为(1405.9±650.2)、(2314.6±710.3)和(6039.9±3 338.4)ng·h·mL-1.药物不良反应主要为面色潮红、头痛或头晕等,程度均为轻度.结论 连续3天,每天1次,口服枸橼酸爱地那非30～60 mg对健康受试者是安全的,爱地那非在体内无明显蓄积;在30、45 mg时,Cmax和AUC0-t与剂量成比例增加;而在60 mg时,呈非线性药代动力学特征.     

Pharmacokinetics of moxisylyte in healthy volunteers after intravenous and oral administration.

The concentration-time profiles of metabolites of moxisylyte, an alpha-blocking agent, in the plasma and urine of 12 healthy volunteers were investigated after intravenous (iv) and oral (two formulations) administration. The study was conducted with an open, randomized Latin squares design. Plasma and urine levels of moxisylyte and its biotransformation products were assayed by a specific HPLC method with fluorescence detection. Plasma levels declined in a monophasic or biphasic pattern depending on the subject. Two metabolites, conjugated desacetylmoxisylyte (DAM) and conjugated monodesmethylated DAM (MDAM), were found in plasma and urine. Unconjugated DAM was found in plasma only after iv administration. The apparent elimination half-lives of unconjugated DAM, conjugated DAM, and MDAM were 0.86, 1.7, and 3 h, respectively. The total amounts of metabolites (expressed as the equivalent of DAM) excreted in the urine were 75% after i.v. administration and 68 and 69% after oral administration of the two formulations. Oral absorption appeared to be complete for the two treatments. There was no statistical difference between the two oral formulations studied.     

单剂口服盐酸吡格列酮片在健康人体的药代动力学

目的研究健康人体单剂量口服盐酸吡格列酮片(胰岛素增敏剂)的药代动力学。方法24名健康男性志愿者单次口服盐酸吡格列酮片30mg,用HPLC-MS/MS同时测定血浆中吡格列酮及其活性代谢产物的浓度,计算其主要药代动力学参数。结果吡格列酮:Cmax为(1504.9±447.8)ng.mL-1;tmax为(1.46±0.69)h;t1/2Ke为(7.58±3.21)h;AUC0-48为(11.22±2.60)μg.h.mL-1。吡格列酮代谢物M-Ⅲ:Cmax为(249.4±82.7)ng.mL-1;tmax为(11.94±6.14)h;t1/2Ke为(20.09±4.13)h;AUC0-120为(10.90±3.55)μg.h.mL-1。吡格列酮代谢物M-IV:Cmax为(487.2±108.6)ng.mL-1;tmax为(13.33±5.23)h;t1/2Ke为(21.07±3.99)h;AUC0-120为(22.78±5.04)μg.h.mL-1。结论健康人体单剂量口服盐酸吡格列酮片剂后,吡格列酮代谢物M-Ⅲ和M-IV的达峰时间约为12～13h,峰浓度分别约为吡格列酮的16%和32%,AUC0-120分别约为吡格列酮AUC0-48的97%和203%。     

单次静滴双氢青蒿素在健康人体的药代动力学和安全性

目的 研究注射用双氢青蒿素(抗疟有效成分)单次静脉滴注后在中国健康人体的药代动力学和安全性.方法 30名健康受试者随机分为3组,分别单次静脉滴注双氢青蒿素40、80和160 mg,用液相色谱一串联质谱法测定血浆中双氢青蒿素浓度,用WinNonLin软件根据非房室模型计算药代动力学参数.试验过程中密切观察不良事件.结果 3组受试者分别单次静滴双氢青蒿素40、80、160 mg的主要药代动力学参数:Cmax分别为(561.5±127.4)、(1080±210)、(2533±503)ng·mL-1,t1/2分别为(1.69±0.52)、(1.88±0.66)、(1.92±0.53)h,AUC0-t分别为(575.6±98.7)、(1370±289)、(2893±649)ng·mL-1·h;Cmax和AUC0-t与剂量的线性关系良好,随给药剂量的增加成比例增加.试验过程中未出现严重不良事件.结论 单次静滴双氢青蒿素在中国健康受试者的体内过程符合线性药代动力学特征,剂量在40～160 mg较安全.     

Pharmacokinetics of tenoxicam after oral administration in healthy human subjects of various single doses

Single oral dose pharmacokinetics of tenoxicam in the dose range intended for therapeutic application of the drug have been defined in healthy human subjects. Twelve male volunteers were given, in random fashion, oral administration of 10, 20 or 40 mg of tenoxicam. Plasma drug levels were determined by a standard HPLC method with U.V. detection. Model-independent analysis showed the clearance, elimination half-life and apparent volume of distribution to be independent of dose with mean values of 0.096 L/h, 76 h and 9.2 L respectively. Interindividual variation was six-fold and individual variation less than two-fold. Similar values for kinetic parameters were obtained by model-dependent methods. The pharmacokinetics of oral tenoxicam were linear in the 10-40 mg dose range and the single dose data predict five-fold accumulation for once daily administration.