Pharmacokinetics of dipyridamole-beta-cyclodextrin complex in healthy volunteers after single and multiple doses.

Dipyridamole is a well known anti-aggregating agent characterized by poor water solubility as well as scant and variable bioavailability. Recently, the compound was complexed with beta-cyclodextrin forming a molecular encapsulation resulting in better oral absorption and stronger biological activities in animals. In the present study, a randomized double blind cross-over comparison between dipyridamole-beta-cyclodextrin complex (dip-beta-CD) and dipyridamole was performed in 12 healthy subjects after single (75mg) and multiple oral treatments (75mg TID). Dip-beta-CD showed better bioavailability and less interindividual variability than dipyridamole either after single or multiple doses. In particular, dip-beta-CD had a greater AUC and Cmax, and a smaller Tmax even at the steady state. In addition, 100% of the subjects receiving a single dose of dip-beta-CD, as compared to 66.7% of those treated with dipyridamole, had plasma levels superior to 1 microgram/ml (which is the supposed anti-aggregating threshold level). In contrast, 0 and 33.03% of the subjects showed plasma levels superior to 2.5 micrograms/ml (which might cause the appearance of side-effects) on the 7th day of the multiple treatment with dip-beta-CD and dipyridamole, respectively. In fact, the subjects presenting higher levels after uncomplexed dipyridamole also complained of headache and/or dizziness on occasion. No adverse side effects were reported for dip-beta-CD.     

Pharmacokinetics of aprepitant after single and multiple oral doses in healthy volunteers

Aprepitant is the first NK1 receptor antagonist approved for use with corticosteroids and 5HT3 receptor antagonists to prevent chemotherapy-induced nausea and vomiting (CINV). The effective dose to prevent CINV is a 125-mg capsule on day 1 followed by an 80-mg capsule on days 2 and 3. Study 1 evaluated the bioavailability of the capsules and estimated the effect of food. The mean (95% confidence interval [CI]) bioavailabilities of 125-mg and 80-mg final market composition (FMC) capsules, as assessed by simultaneous administration of stable isotope-labeled intravenous (i.v.) aprepitant (2 mg) and FMC capsules, were 0.59 (0.53, 0.65) and 0.67 (0.62, 0.73), respectively. The geometric mean (90% CI) area under the plasma concentration time curve (AUC) ratios (fed/fasted) were 1.2 (1.10, 1.30) and 1.09 (1.00, 1.18) for the 125-mg and 80-mg capsule, respectively, demonstrating that aprepitant can be administered independently of food. Study 2 defined the pharmacokinetics of aprepitant administered following the 3-day regimen recommended to prevent CINV (125 mg/80 mg/80 mg). Consistent daily plasma exposures of aprepitant were obtained following this regimen, which was generally well tolerated.     

健康志愿者单次和多次口服美敏伪麻缓释胶囊的药动学研究

目的研究美敏伪麻缓释胶囊经单、多次给药后的药动学特征,评估其在健康志愿者体内的安全性。方法 22例受试者随机、开放试验设计,研究单、多次给药药动学特征。血浆中氯苯那敏、伪麻黄碱、右美沙芬、右啡烷采用LC-MS/MS法测定,药动学参数采用Win Nonlin软件计算。安全性特征以记录到的所有不良事件来进行评价。结果整个研究过程中没有严重不良事件报告。单次口服美敏伪麻缓释胶囊后,伪麻黄碱、氯苯那敏、右美沙芬和右啡烷均在3~5 h达峰,t1/2分别为6.30±1.17、23.3±6.91、10.4±2.19、8.62±3.04 h,Cmax分别为203±40.4、5.05±1.39、4.29±3.95、1.95±0.72 ng/m L,AUClast分别为2 050±559、137±47.5、61.3±67.5、17.2±6.58μg·h/L,AUCinf分别为2 140±570、161±63.8、17.6±6.65、62.8±69.3μg·h/L。在2次/d,连续给药4 d后基本达到稳态血药浓度,伪麻黄碱、氯苯那敏、右美沙芬和右啡烷的Cmax、Cmin、AUCtau,ss与单次给药比较均有不同程度的升高,波动系数的平均值为107%~271%。结论美敏伪麻缓释胶囊多次给药后4 d达到稳态血药浓度,暴露均较单次给药后有所增高,在健康志愿者体内安全性良好。     

Pharmacokinetics of cefoperazone after single and multiple doses

The pharmacokinetics of cefoperazone was determined following single and multiple intravenous and intramuscular administrations in man. Ten subjects at each dose level were given eleven successive doses, at 12 h intervals of 500 and 1000 mg i.m. and i.v.. Serum concentrations and urinary excretion were determined in all subjects after the first, fifth and eleventh doses. The first i.m. doses yielded mean peak serum levels of 37 micrograms/ml and 76 micrograms/ml at 1.0 h after injection. The first i.v. doses yielded mean serum levels of 93 and 180 micrograms/ml at 5 min after the injection. No tendency toward drug accumulation was observed on multiple dosage. The pharmacokinetics could be described by a linear, open, two-compartment model of drug distribution. The terminal serum half-life (2.1-2.4 h after i.v. doses and 2.6-2.8 h after i.m. doses) remained essentially constant over the period of the study by dose levels. The no-significant differences of areas under the curve between the two routes, at two doses, show the absolute bioavailability of cefoperazone was about 95% following i.m. administration. The high binding to serum proteins (90%) influences favourably the pharmacokinetic parameters of cefoperazone. It yielded high and prolonged serum concentrations and has very useful distribution properties. These favourable properties, together with its good antibacterial activity, suggest that cefoperazone will be effective in treating bacterial infections in human beings.     

Pharmacokinetics of co-trimazine after single and multiple doses

Plasma and urinary levels of trimethoprim (TMP), sulfadiazine (SDZ) and N4-acetylsulfadiazine (N4-SDZ) were determined after administration of 1 g co-trimazine (equivalent to 180 mg TMP and 820 mg SDZ) (Kombinax) as a single dose and again once daily for 7 days to 6 normal subjects. Both TMP and SDZ were rapidly absorbed from the gastrointestinal tract with peak plasma levels being achieved within 4 h in all subjects. Elimination half-lives ranged from 8 to 13 h for TMP and from 9 to 15 h for SDZ. Approximately 50% of the administered dose of SDZ was recovered in urine within 24 h of the single dose (32% as unchanged drug and 17% as the N4-acetylmetabolite). For TMP, the urinary recovery during the 24 h following the single dose averaged 39%. Mean plasma levels of TMP, SDZ and N4-SDZ at steady state were moderately higher than those observed after a single dose, but no change in absorption or disposition kinetics of these compounds was seen after repeated dosing.     

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.     

注射用法罗培南钠的单剂量和多剂量药代动力学研究

目的考察单次和连续静脉滴注法罗培南钠注射液后健康人体内的药动学过程。方法12名健康受试者随机交叉单剂量静脉滴注给药100,200,300,600mg,单剂量试验结束后进人多剂量试验,8名受试者静脉滴注给药每次200mg,每日3次,连续给药7d,用高效液相色谱法测定血浆和尿中法罗培南的浓度,并采用药动学程序对试验数据进行处理,求算有关药动学参数。结果12名健康受试者单剂量静脉滴注法罗培南注射液后,主要药动学参数Cmax分别为（8．42±1．96）mg／L,（16．64±3．09）mg／L,（24．73±3．58）mg／L,（44．43±3．93）mg／L,T1/2分别为（1．72±0．72）h,（1．60±0．33）h,（1．56±0．21）h,（1．36±0．09）h,AUCOJ分别为（13．90±2．96）mg·h／L,（26．98±5．75）mg·h／L,（38．29±5．29）mg·h／L,（70．58±10．33）mg·h／L,12h累积尿药排泄率分别为31．4％,31．5％,30．5％,34．9％,多次静脉滴注后的主要药动学参数Cmax,T1/2,AUC0-4分别为（15．83±3．96）mg／L、（1．11±0．27）h、（21．93±3．59）mg·h／L,血药浓度波动系数和Gav分别为（5．34±1．30）和（2．74±0．45）mg／L,12h累积尿药排泄率为40．5％。结论单次给药在100～600mg剂量范围内法罗培南呈线性消除,性别对法罗培南的药代动力学过程无影响,肾脏是法罗培南的主要排泄器官,连续多次给药在体内无蓄积,     

Pharmacokinetics of terlipressin after single i.v. doses to healthy volunteers

The pharmacokinetics of triglycyl-lysine-vasopressin (TGLVP) were studied in healthy male volunteers after single i.v. injections of 5, 10 and 20 micrograms/kg b. wt. The half-life of distribution and elimination was 8 and 50 min, respectively. The volume of distribution was 0.7 l/kg b.wt. and the plasma clearance 9 ml/kg b.wt./min. These values are different from those for arginine-vasopressin and lysine-vasopressin (LVP) but confirm to some extent earlier results on TGLVP. No dose-dependent changes of the pharmacokinetics of TGLVP were evident. The LVP formation after TGLVP is described in principle using a combination of pharmacokinetic and pharmacodynamic data. Therapeutically the results in this study suggest a 4-hour interval between injections.     

Diltiazem pharmacokinetics in elderly volunteers after single and multiple doses

In young healthy volunteers diltiazem does not have linear kinetics between single and multiple doses. Elimination half-life increases and gives AUC's and Cmax higher than those predicted from single dose data. Kinetics of diltiazem were assessed in 16 healthy elderly after a single 60 mg dose and in 24 healthy elderly after 60 mg every 8 h for 7 days. Thirteen participants completed both studies. Elimination half-life, AUC0-24, AUC0-infinity, and Cmax were (mean +/- SE) 7.4 (1.2) h, 349 (34) ng/ml.h, 392 (44) ng/ml.h, and 43 (5) ng/ml respectively after a single dose. After multiple doses elimination half-life, AUC0-48, AUC0-infinity, Cmax and Cmin were respectively 5.7 (0.3) h, 974 (107) ng/ml.h, 1022 (108) ng/ml.h, 102 (7) ng/ml and 43 (5) ng/ml. Exploratory statistics on the 13 volunteers common to both studies showed that the ratio of AUC desacetyl-diltiazem (DAD)/AUC diltiazem rose between single and multiple doses while elimination half-life of both diltiazem and N-desmethyl-diltiazem (MA), tmax, and AUC MA/AUC diltiazem were not affected. The conclusion of this study is that elimination half-life of diltiazem does not increase in elderly between single and multiple doses, possibly due to an increased biotransformation into DAD.     

单剂量和多剂量口服布洛伪麻那敏干混悬剂在健康人体的药代动力学

目的研究布洛伪麻那敏干混悬剂(抗感冒药)在健康成年志愿者体内的药代动力学。方法3个单剂量组及1个多剂量组口服给药,用高效液相色谱-紫外检测法测定给药后不同时间布洛芬血药浓度,高效液相色谱-串联质谱法测定给药后不同时间伪麻黄碱和氯苯那敏血药浓度。用DAS Ver 2.0计算药代动力学参数并进行统计分析。结果3组单剂量及连续口服布洛芬(单剂:200,400,600 mg;连续:200 mg)、伪麻黄碱(单剂:30,60,90 mg;连续:30 mg)及氯苯那敏(单剂:2,4,6 mg;连续2 mg)7天后的主要药代动力学参数(tmax,Cmax,AUC0-t,AUC0-∞,t1/2等)结果显示,布洛芬、伪麻黄碱和氯苯那敏血药浓度-时间曲线拟合结果均符合一室模型,体内过程均呈线性动力学特征。结论连续多次给药,3组分都不存在药酶诱导或抑制现象。     

Diltiazem pharmacokinetics in elderly volunteers after single and multiple doses

In young healthy volunteers diltiazem does not have linear kinetics between single and multiple doses. Elimination half-life increases and gives AUC's and Cmax higher than those predicted from single dose data. Kinetics of diltiazem were assessed in 16 healthy elderly after a single 60 mg dose and in 24 healthy elderly after 60 mg every 8 h for 7 days. Thirteen participants completed both studies. Elimination half-life, AUC0-24, AUC0-infinity, and Cmax were (mean +/- SE) 7.4 (1.2) h, 349 (34) ng/ml.h, 392 (44) ng/ml.h, and 43 (5) ng/ml respectively after a single dose. After multiple doses elimination half-life, AUC0-48, AUC0-infinity, Cmax and Cmin were respectively 5.7 (0.3) h, 974 (107) ng/ml.h, 1022 (108) ng/ml.h, 102 (7) ng/ml and 43 (5) ng/ml. Exploratory statistics on the 13 volunteers common to both studies showed that the ratio of AUC desacetyl-diltiazem (DAD)/AUC diltiazem rose between single and multiple doses while elimination half-life of both diltiazem and N-desmethyl-diltiazem (MA), tmax, and AUC MA/AUC diltiazem were not affected. The conclusion of this study is that elimination half-life of diltiazem does not increase in elderly between single and multiple doses, possibly due to an increased biotransformation into DAD.     

Pharmacokinetics of moxonidine after single and repeated daily doses in healthy volunteers

The pharmacokinetics of the centrally acting alpha-2 agonist moxonidine were investigated in 12 healthy male subjects after single and repeated oral doses (q12h for five days) of moxonidine 0.2 mg. Plasma concentration-time data followed the general characteristics of a one-compartment model with first-order absorption. Peak plasma concentrations of 1.29 +/- 0.32 ng/mL were achieved 0.74 +/- 0.35 hours after ingestion of a 0.2-mg tablet. The terminal half-life of elimination was 2.12 +/- 0.58 hours. The oral clearance (CL/F) amounted to 830 +/- 171 mL/min with renal elimination being the major route of elimination. No significant differences in pharmacokinetic parameters could be observed following repeated dosing over five days.     

Pharmacokinetics of lipoic acid in healthy Chinese volunteers after single and multiple doses of Lipoic acid dispersible tablets

This study aimedto evaluate the pharmacokinetics for lipoic acid (LA) after oral administration of 12 healthy Chinese volunteers with single and multiple-dose of lipoic acid dispersal tablets using a liquid chromatography-temdend mass spectrometry (LC-MS/MS) methods. In single-dose study, healthy Chinese male and female volunteers received three dose levels at 0.2, 0.3, and 0.4 g of LA dispersal tablets with a 3×3 Latina square design. In multiple-dose study, 12 healthy Chinese volunteers received orally a 0.1 g of LA dispersible tablet three times daily for 6 consecutive days and 0.3 g once on day 7. The results showed that pharmacokinetics of LA fitted a two-compartment open model. The values of area under the curve (AUC) increased proportionally within the range of 0.2–0.4 g, while the Vd/F, CL/F, MRT, t_1/2 and t_max of LA were similar at three dose levels. The steady-state pharmacokinetic parameters of LA were similar to those following a single dose and no accumulation was found following multiple-dose of LA dispersal tablets.     

Pharmacokinetics of diclofenac and five metabolites after single doses in healthy volunteers and after repeated doses in patients

1. The kinetics of diclofenac (I) and five of its metabolites (II-VI) were investigated in three healthy volunteers and in six patients. Compounds I-VI were measured by capillary column gas chromatography in plasma and urine. 2. After a single 100 mg dose of diclofenac sodium to volunteers, the drug was absorbed rapidly and showed peak plasma levels of 10-12 nmol/g. The maximum concentrations of five metabolites were comparatively low (0.36-2.94 nmol/g). The mono- and dihydroxy metabolites (II-V) had apparent terminal half-lives similar to that of I (1-3 h), but the hydroxymethoxy metabolite (VI) had a half-life of about 80 h. Renal elimination of VI within 96 h was about 1% of dose and that of I-VI was 36% (free plus conjugated). 3. Following daily treatment with 2 x 75 mg of an experimental sustained release formulation to patients for 6-10 months, steady-state trough concentrations of I-V in plasma were low (average values: 0.23-0.57 nmol/g). The mean trough concentration of VI was comparatively higher at 3.69 +/- 0.91 nmol/g presumably reflecting its accumulation. Despite this it is unlikely to contribute to the drug's therapeutic activity, since it has been shown in laboratory tests to be devoid of anti-inflammatory activity.     

Pharmacokinetics of chlorthalidone in the elderly after single and multiple doses

To investigate the discrepancy between the apparent pharmacokinetic disposition of (+)-penicillamine in plasma and urine, the spontaneous degradation of (+)-penicillamine was studied in acidified and non-acidified urine. Degradation was prevented by acidification. The oxidized metabolites were converted to reduced (+)-penicillamine by electrolysis.     

铝镁匹林片单剂量和多剂量人体药动学研究

目的:研究单剂量和多剂量铝镁匹林片(每片含阿司匹林81 mg,甘羟铝11 mg,重质碳酸镁22 mg)的人体药动学特征。方法:27名健康受试者随机等分成81,162和324 mg·d~(-1)三组,每日口服规定剂量的铝镁匹林片,连续7 d。采用HPLC-MS-MS法测定血浆阿司匹林和水杨酸浓度。结果:阿司匹林的T_(max)约30 min,t_(1/2)为17．4～29．8 min;水杨酸的t_(1/2)为3～4 h,T_(max)为30～60 min;各剂量组的C_(max)AUC,T_(max),t_(1/2)和Cl/F在给药后d1和d7均无显著性差异,t_(1/2)和Cl/F在三组间无显著性差异。结论:在本研究剂量范围内,阿司匹林和水杨酸呈线性动力学,连续服药未见体内蓄积。     

石杉碱甲缓释片多剂量给药健康人体药代动力学研究

目的：评价石杉碱甲缓释片多剂量给药在健康人体药代动力学规律。方法：采用双周期自身随机交叉试验设计。24名健康志愿者多次口服试验药石杉碱甲缓释片或参比制剂,采用LC-MS/MS测定血浆中药物浓度,药动学参数采用DAS软件处理获得。结果：试验制剂石杉碱甲缓释片组与参比制剂石杉碱甲普通片组的Cssmin分别为（0.54±0.21）和（0.79±0.20）ng/mL,Cssmax分别为（1.65±0.45）和（1.83±0.37）ng/mL,Css分别为（1.05±0.28）和（1.22±0.28）ng/mL,tmax分别为（3.5±1.9）和（1.1±0.4）h,AUC0-t（ss）分别为（31±8）和（35±9）ng·mL^-1·h,AUC0-∞（ss）分别为（37±10）和（41±11）ng·mL^-1·h,AUCss分别为（25±7）和（15±3）ng·mL^-1·h;相对于参比制剂,受试制剂的生物利用度Fss0-tn为（88±12）%。受试制剂和参比制剂的AUC0-t和AUC0-∞经对数转换后进行方差分析,两制剂间变化相近（P〉0.05）,受试制剂tmax明显比参比制剂有所延长（P〈0.05）,明显具有缓释的特征。结论：试验制剂石杉碱甲缓释片具有明显的缓释特征。     

Pharmacokinetics of fluoride in man after single and multiple oral doses

Summary The doses of fluoride (F) recommended in the literature for caries prevention and for the treatment of osteoporosis vary. This partly reflects inadequate knowledge of F pharmacokinetics. In the present study various single and multiple oral doses of F were given to eight volunteers, who had a strictly controlled F intake in the diet. The resulting plasma and parotid saliva concentrations as well as urinary output of F were measured. The plasma data fitted a two-compartment open model with a -slope half-life ranging between 2 and 9 h. Plasma clearance was 0.15±0.02 (SD) liter/kg/h. Data from the highest dose (10 mg) were fitted to both two- and three-compartment models, and there was no significant difference between them. Multiple doses of F 3.0 or 4.5 mg yielded steady state concentrations ranging from 54 to 145 ng/ml. About 50 per cent of the given dose was recovered in the urine, which is indicative of considerable accumulation in the body. The saliva F/plasma F concentration ratio was 0.64 with a coefficient of variation of 5%.     

Pharmacokinetics of butobarbital after single and multiple oral doses in man

Summary A method is described for the assay of therapeutic levels of butobarbital (5-ethyl-5-n-butylbarbituric acid) in human plasma, which involves a single extraction step followed by gas chromatography with alkali flame ionization detection. The pharmacokinetics of butobarbital were studied in five healthy volunteers after oral administration of 200 mg. Plasma concentrations were determined at regular intervals up to 96 h and the data were fitted by non-linear, least squares regression analysis according to one-compartment kinetics. The average lag time was 0.11 h and the absorption half-life 0.21 h. The elimination half-life varied from 33.6 to 41.5 h with an average of 37.5 h. Four of the volunteers participated in a study of multiple dosing (every 24 h) during which substantial accumulation of butobarbital was observed. The elimination half-life after termination of drug administration had decreased to about 20–25% of its initial value, probably because of enzyme induction. It was concluded that butobarbital could not be regarded as a suitable drug for treatment of insomnia, since CNS depressant effects were likely to persist into the following day. Repeated administration of butobarbital should be avoided and its incidental use restricted to patients who require day-time sedation.     

Pharmacokinetics of mifentidine after single and multiple oral administration to healthy volunteers.

1. The pharmacokinetics of mifentidine, a new long acting histamine H2-receptor antagonist, were studied using two protocols. 2. In one study, on 5 different days six normal male subjects were given 2.5, 5, 10, or 20 mg mifentidine or placebo orally 60 min before starting a 3 h continuous gastric aspiration during which time blood samples were taken for measurement of mifentidine concentration. 3. The area under the curves of mifentidine plasma levels (AUC) vs time for the four doses was linearly related to the dose for each individual subject (r = 0.972, P less than 0.001). After doses of 2.5, 5, 10 and 20 mg, mifentidine reduced hydrogen ion output by respectively 36, 37, 60 and 75% and secretory volume by 1, 17, 40, and 47%. The effects at the two highest doses were statistically significant. AUC was correlated positively with the percentage reduction in hydrogen ion output (r = 0.802, P less than 0.001) and volume (r = 0.834, P less than 0.001) over a 3 h period. 4. In the second study, the pharmacokinetics were evaluated after once-daily treatment for 14 days in seven subjects given 10 mg and in seven others subjects given 20 mg. 5. After multiple dosing, renal clearance was similar for the two doses (11.6 +/- 2.11 l h-1 for the low dose and 17.0 +/- 2.0 l h-1 for the high dose). Plasma half-life (t1/2 lambda 2) was 16.0 +/- 3.0 h after the 10 mg dose and 11.9 +/- 1.2 h after 20 mg.(ABSTRACT TRUNCATED AT 250 WORDS)