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1.
Summary The bioavailability of ketanserin has been examined in a cross-over experiment in 21 elderly subjects (aged 59–72 years) by administration of tablets (40 mg), solution (40 mg) and injectable solution (10 mg). After two weeks of treatment with 40 mg ketanserin tablets further 18 blood samples for analysis were collected under steady-state conditions. Plasma levels were measured by HPLC. The absolute bioavailability of ketanserin tablets was 52.7%; their relative bioavailability compared to a solution containing an equal quantity of active compound was 85.5%. Therefore, the low absolute bioavailability of ketanserin cannot be attributed to the formulation.The active compound was rapidly liberated from the tablet, reaching a peak of 103.8 ng/ml after 0.97 h. Individual plasma level-time curves were fitted to an open three compartment model and a half-life of 17.7±7.26 h was calculated for the terminal elimination phase. An average terminal elimination half-life of 15.4±4.2 ng/ml was found after administration of the ketanserin solution.Multiple dosing with 40 mg tablets b.d.s. resulted in an AUC over one dosing interval at steady-state of 666±201 ng × h/ml. The AUC extrapolated to infinity was 1200±405 ng × h/ml for the last tablet. This is 1.8-times the AUC in one dosing interval, and 2.3-times the AUC of a single dose. Under steady-state conditions, the mean peak plasma level was 155.1 ng/ml (1.08 h after dosing) and the terminal half-life was 19.1±5.1 h.For the metabolite ketanserinol terminal half-lives of 21.4 h after a single tablet and 31.0 h after discontinuation of multiple dosing were calculated. Compared to the parent compound there was much more marked accumulation of ketanserinol.Despite moderate accumulation and prolongation of the terminal half-life of ketanserin under steady-state conditions, dosage adjustment is not required in elderly people. First-pass metabolism and bioavailability remained in the range found in previous studies of ketanserin in young subjects.  相似文献   

2.
Summary The pharmacokinetics of bevantolol were examined following single and repeated oral doses to young and elderly volunteers. Following administration of a single 200-mg bevantolol tablet mean maximum plasma bevantolol concentrations in young and elderly subjects were 1690 ng/ml and 1810 ng/ml, respectively. Maximum bevantolol concentrations occurred approximately 1.1 h postdose in both young and elderly subjects. There were no significant differences in mean steady state bevantolol concentrations on Day 14 between young and elderly subjects. However, disproportionate increases in Cmax, and in AUC, but not in tmax values were observed between Days 1 and 14.On Days 1 and 14, most young and elderly subjects exhibited monoexponential decline in bevantolol plasma concentrations after absorption phase. In those subjects Day 14 elimination half-lives in young and elderly were 1.9 and 2.2 h, respectively. In subjects who exhibited biexponential decline in bevantolol, an age effect in elimination became apparent, on Day 14 elimination half-lives were 5.7 and 11.2 h in young and elderly subjects, respectively. Bevantolol Metabolite III concentrations were observed in plasma of some subjects during the first 6 h after dosing. At steady-state AUC (0-ldc) values for the metabolite were less than 2% those of bevantolol.Bevantolol plasma levels accumulate to a small extent with repeated 200 mg daily doses. This is probably due to the contribution of a late and more persistent terminal elimination phase that was discernable in only certain individuals.  相似文献   

3.
Summary The duration and extent of cardiac beta-blockade and their relationship to propranolol pharmacokinetics were assessed in nine healthy volunteers. Each subject received 160 mg of regular propranolol (R), 160 mg of sustained-release propranolol (SR) and no drug (control), both as single doses and once daily for 7 days.After single doses and at steady-state, both products caused a decrease in exercise heart rate for at least 24 h, compared to control. The time course of effect was similar to the time course of serum propranolol concentration. The oral clearance of propranolol decreased from single doses to steady-state for both R and SR; however, the difference achieved statistical significance only for R. These changes were reflected in mean accumulation ratios (AUC steady-state 0–24 h/AUC single dose 0-infinity) of 1.49 and 1.68 for R and SR, respectively.The pharmacokinetic data are consistent with a decrease in intrinsic hepatic clearance of propranolol, leading to an increase in bioavailability at steady-state. Despite a two-fold difference in the bioavailability of R and SR, there was no difference in the area under the effect-time curve at steady-state.Presented in part at the IIIWorld Conference on Clinical Pharmacology and Therapeutics, Stockholm, Sweden, July 1986  相似文献   

4.
目的 研究中国健康受试者单次口服盐酸川丁特罗片(平喘药)的耐受性、安全性和药代动力学.方法 采用剂量递增试验设计,30名健康志愿者随机分为3个剂量组,分别单次口服盐酸川丁特罗片25、50、100μg,观察不良事件,用HPLC-MS/MS测定血浆和尿样中川丁特罗的浓度,用WinNonLin 5.0计算其主要药代动力学参数.结果 30名受试者单次口服盐酸川丁特罗片后,有2名受试者出现2个与研究药物有关的不良事件,程度均为轻度,未经任何治疗自行恢复.未出现严重不良事件.单次口服盐酸川丁特罗片25、50、100 μg的主要药代动力学参数Cmax分别为(12.2±4.2)、(20.0±4.3)、(48.6±14.3)pg·mL-1;tmax分别为(1.1±0.5)、(1.8±1.2)、(1.3±0.4)h;t1/2分别为(19.9±6.4),(18.0±6.7)、(17.7±8.6)h;AUC0-tn分别为(80.5±43.0)、(116.7±57.5)、(215.7±64.5)pg·h·mL-1;Ae分别为(1.7±0.5)%、(2.1±0.8)%、(1.9±0.3)%.结论 中国健康受试者单次口服盐酸川丁特罗片25~100 μg安全、可耐受;且其体内过程呈线性药代动力学特征.  相似文献   

5.
AIMS: The primary objective of this study was to describe the single dose pharmacokinetics of ribavirin in subjects with normal liver function and those with various degrees of stable chronic liver disease. Additionally this study assessed the safety and tolerability of ribavirin in this population. METHODS: Single oral 600 mg doses of ribavirin were administered to healthy male and female volunteers (n = 6) and patients with stable chronic liver disease (n = 17), in a parallel group study. Pharmacokinetic sampling and tolerability assessments were performed up to 168 h post dose. RESULTS: Single oral doses of 600 mg ribavirin were well tolerated by healthy volunteers and patients with varying degrees of hepatic dysfunction. Although mean Cmax increased with the severity of hepatic dysfunction, there was no change in extent of absorption or renal clearance of ribavirin. CONCLUSIONS: There are no pharmacokinetic reasons for initial dose adjustment of ribavirin in patients with hepatic dysfunction.  相似文献   

6.
Abstract

1. Cytisine, a partial agonist for the α4β2-nAChR, is used as a smoking cessation medication. Cytisine’s current dosing is complex and involves taking 1.5?mg several times a day. The aim of this study was to explore the effect of dose on the pharmacokinetics and safety of cytisine after a single dose in healthy adult smokers.

2. Participants were assigned to one of three groups (n?=?6 in each group) to receive a single oral dose of 1.5, 3 or 4.5?mg of cytisine. Blood samples were collected up to 24?h post dose. Pulse, blood pressure and respiratory rate were measured. Adverse effects were recorded.

3. Cytisine reached peak plasma concentration 1–2?h post dose in all participants irrespective of dose, with no dose-dependent changes in the elimination phase. Mean (SD) cytisine exposure (AUC0–24h) were 81.9 (15.8), 181.9 (40.8) and 254.5 (48.1) ng.h/mL following 1.5, 3 and 4.5?mg, respectively.

4. Cytisine appears to have predictable pharmacokinetics following a single dose of up to 4.5?mg and may be safe given as a single 4.5?mg dose, which is threefold greater than the recommended dose taken at one time.

Trial registration: ClinicalTrials.gov identifier: NCT02585024.  相似文献   

7.
To obtain further information about the availability of salmon calcitonin in the biophase compartment that surrounds the receptor site, salmon calcitonin concentrations in plasma and skin blister fluid (SBF) after a single IV dose of 100 IU synthetic salmon calcitonin were compared in 15 healthy volunteers.Serial blood and SBF samples were collected before and up to 8 h after administration and calcitonin was determined by a specific RIA.The maximum concentration in plasma was 225 pg·ml-1 (in the first sample at 15 min), whereas in SBF the mean peak of 84 pg·ml-1 was reached after about 30 min. The distribution of salmon calcitonin into SBF, defined as the ratio of the AUCs in SBF and plasma, was 1.5. The kinetic profiles of salmon calcitonin in plasma and interstitial fluid were different. Calcitonin in plasma peaked and then levelled out, while in SBF it persisted longer than in plasma.This is the first report of the distribution of salmon calcitonin into blister fluid.  相似文献   

8.
Summary Ketanserin is a new antihypertensive agent with affinity to serotonin (5-HT)2 receptors and at higher concentrations also to 1-adrenoceptors. The present study was designed to evaluate the relative functional importance of the antagonism of 1-adrenoreceptors and 5-HT2-receptors in the antihypertensive mechanism of action of ketanserin and analogues after acute administration. In the spontaneously hypertensive rat, ketanserin and the two ketanserin analogues, R56413 and R55667 (which have relatively weaker -adrenolytic properties) were studied with regard to their ability to reduce the blood pressure after acute administration in the conscious rat and their ability to shift the dose response curves for 5-HT and phenylephrine in the pithed rat. The agents tested reduced the blood pressure only in a dose range where they blocked 1-adrenoceptors and there was a striking correlation between the degree of hypotension and the degree of inhibition of the phenylephrine induced pressor responses. 5-HT2-receptor blockade alone did not influence basal blood pressure. However, following pretreatment with R55667 in a low dose the blood pressure reduction to prazosin was enhanced.It is concluded that following acute administration in the rat the major portion of the antihypertensive response to ketanserin is due to an 1-adrenoceptor blockade but that the 5-HT2-receptor blockade contributes.Abbreviations 5-HT 5-hydroxytryptamine - SHR spontaneously hypertensive rat - SNS sympathetic nervous stimulation  相似文献   

9.
Summary The pharmacodynamic and pharmacokinetic profiles of nifedipine and nisoldipine were compared in a double blind, placebo-controlled study. Nisoldipine, 10 mg significantly reduced systolic blood pressure but nifedipine 20 mg retard did not, although both drugs had significant pharmacodynamic effects as evidenced by increased heart rates. The terminal elimination half-life in plasma was similar for both drugs with a mean of 2 h. The pharmacodynamics of nisoldipine were studied in 8 hypertensives following both acute and chronic administration. Antihypertensive efficacy was demonstrated after acute dosing and was maintained over 4 weeks of twice daily treatment as monotherapy.  相似文献   

10.
AIMS: Fosinoprilat, the active product of fosinopril, is eliminated by an hepatic pathway in addition to the renal pathway shared by other angiotensin converting enzyme inhibitors (ACEIs). This study aimed to determine whether impaired renal function affects the pharmacokinetics and pharmacodynamics of a combination of fosinopril and hydrochlorothiazide (HCTZ). METHODS: The study had a parallel-group design comparing patients with renal impairment and body-mass-index-matched normal controls. The study was done in a University clinic in 13 patients with renal impairment (mean creatinine clearance 55.7+/-15.6 ml min-1 1.73 m-2 ) and 13 age-, sex-, and body-mass-index-matched normal controls (mean creatinine clearance 102.4+/-8.9 ml min-1 1.73 m-2 ). All patients and normal controls received fosinopril sodium 20 mg and HCTZ 12.5 mg as a daily oral administration on days 1-5. Non-compartmental pharmacokinetic parameters of fosinoprilat and HCTZ were determined from blood and urine samples obtained over 48 h starting on Day 1 (single dose) and Day 5 (steady state): maximum serum concentration (Cmax ), time to maximum serum concentration (tmax ), area under the serum concentration-time curve during the dosing interval (AUC), cumulative urinary excretion (CUE) and the accumulation index (AI; ratio of AUC-day 5/AUC-day 1). Pharmacodynamic parameters were also measured over 24 h on day 1 and over 48 h on day 5: serum ACE activity and arterial blood pressure. RESULTS: Fosinoprilat pharmacokinetic parameters on day 1 in renally impaired vs normal patients: Cmax=387+/-0.19 vs 324+/-0.25 ng ml-1 (P=0.07); tmax=3.5 vs 3.0 h (P=0.58); AUC=3510+/-0.29 vs 2701+/-0.35 ng ml-1 h (P=0. 072); CUE=5.08+/-2.70 vs 7.40+/-2.56% (P=0.009). Fosinoprilat parameters on day 5: Cmax=517+/-0.40 vs 357+/-0.19 ng ml-1 (P=0. 007); tmax=3.0 vs 3.0 h (P >0.99); AUC=4098+/-0.43 vs 2872+/-0.30 ng ml-1 h (P=0.027); CUE=6.81+/-3.53 vs 8.10+/-2.80% (P=0.068). AI=1. 17+/-0.33 vs 1.06+/-0.23 (P=0.29). In both groups ACE inhibition and blood pressure response were similar over 24 h and slightly greater 48 h after last dosing. CONCLUSIONS: In renally impaired subjects fosinopril and HCTZ can be coadministered without undue increases in fosinoprilat concentrations or any clinically significant pharmacodynamic effects. This is probably due to the dual excretory pathways for fosinoprilat.  相似文献   

11.
Summary The effects of pretreatment with a seven day course of ciprofloxacin on pharmacokinetics and pharmacodynamics of an intravenous (5 mg) dose of diazepam were investigated in a group of 12 healthy volunteers in a double-blind placebo-controlled crossover study.Ciprofloxacin pretreatment significantly reduced diazepam CL (without ciprofloxacin: 19.5 ml·h–1kg–1; with ciprofloxacin: 12.3 ml·h–1kg–1). Diazepam t1/2 was also prolonged (without ciprofloxacin: 36.7 h; with ciprofloxacin: 71.1 h), but volume of distribution was unaltered (without ciprofloxacin: 1.1 l·kg–1; with ciprofloxacin: 1.1 l·kg–1).However, no significant changes were detected in psychometric tests of digit symbol substitution, tapping rate and short memory, as well as levels of concentration, vigilance and tension measured by visual analogue scales.  相似文献   

12.
Summary The time-dependent concentration curves of sulphadimethoxine in plasma and cantharidin-induced skin blister fluid have been evatuated following a single oral dose of 1 g.In contrast to other drugs, sulphadimethoxine exhibited two-stage penetration into the blister fluid, the second peak concentration being higher than the first. The maximum plasma concentration of 94.1 mg·l–1 was observed after 4 h, and in skin blister fluid the first peak of 25.6 mg·l–1 was found after 7 h, and the second of 58.0 mg·l–1 occurred after 30 h. The penetration of sulphadimethoxine into skin blister fluid, defined as the ratio of the AUC there to that in plasma was 0.748.The results suggest that sulphadimethoxine penetrates into skin blister fluid to a great extent from plasma and achieves concentrations exceeding the MIC for susceptible pathogens, but it requires a relatively long time to do so.  相似文献   

13.
格列吡嗪血药浓度测定及中国健康人体药物动力学研究   总被引:2,自引:1,他引:2  
目的建立反相高效液相色谱法测定人血浆中格列吡嗪浓度的方法,以及研究格列吡嗪片在中国健康人体的药物动力学。方法以KiomasalC18(4.6mm×125mm,5μm)为分析柱,乙腈0.05mol·L-1磷酸二氢钾缓冲液(38∶62,v/v)为流动相,流速为1.0mL·min-1,二极管阵列检测器(DAD)检测波长为225nm,艾司唑仑为内标,测定血浆中格列吡嗪的浓度。结果在浓度20.4~2040ng·mL-1,格列吡嗪和内标峰面积比值与浓度呈良好的线性关系(r=0.9993)。格列吡嗪高、中、低3个浓度的平均回收率分别为(105.2±4.4)%、(92.9±5.0)%、(109.4±8.4)%;日内、日间RSD均小于10%。药物动力学研究表明,格列吡嗪体内过程符合一室模型,体内药物tmax、cmax、t1/2(Ke)、AUC0~24分别为(1.6±0.3)h、(728.5±229.7)ng·mL-1、(3.3±0.9)h、(4130.5±1383.0)ng·h·mL-1。结论方法简便、快速准确、重现性好,可用于格列吡嗪的药物动力学研究。  相似文献   

14.
单剂口服盐酸托烷司琼胶囊的人体药代动力学   总被引:3,自引:0,他引:3  
目的 研究口服单剂盐酸托烷司琼胶囊人体药代动力学。方法 22名健康志愿者口服盐酸托烷司琼胶囊,18例剂量为10 mg, 4例剂量为20mg,于给药后设定时间点采血, 用反相高效液相色谱法-二极管阵列紫外法测定受试者血浆中的盐酸托烷司琼浓度, 并对盐酸托烷司琼的血药浓度-时间数据进行拟合,求算其药代动力学参数。结果 10和20 mg剂量组盐酸托烷司琼胶囊的药代动力学参数分别为:达峰时间tmax为(2.53±0.52)和(2.35±0.90) h;Cmax为(10.16±2.89) 和(19.56±4.04) mg.L-1,曲线下面积AUC0-24h 分别为(113.61±40.34)和(213.36±42.53) mg.h.L-1。结论 单剂量给药,盐酸托烷司琼胶囊在志愿者体内分布及消除较快,且Cmax及AUC与剂量成正比。  相似文献   

15.
The pharmokinetics of isradipine in hypertensive subjects   总被引:1,自引:0,他引:1  
Summary In conjunction with a multicentre clinical trial of the calcium antagonist isradipine in hypertension, pharmacokinetic and pharmacodynamic studies were conducted in 9 subjects. An initial dose of 5 mg (capsule formulation) of isradipine was given orally. The mean Cmax, tmax and AUC(0–8) were 6.0 ng · ml–1, 1.5 h and 15.1 h · ng · ml–1 respectively. Seven subjects repeated the study at steady state after 10 week's dose titration with isradipine. Cmax, tmax and AUC(0–8) were 3.7 ng · ml–1, 1.2 h and 12.2 h · ng · ml–1 respectively indicating that the drug does not accumulate over time.Control of blood pressure paralleled plasma isradipine concentrations which suggested that the drug should be given at least twice daily. Pharmacokinetic studies performed in conjunction with clinical trials can provide valuable information about the patterns of drug response.  相似文献   

16.

Aims

This open label study was conducted to assess the effect of renal impairment (RI) on the pharmacokinetics (PK) of peginterferon lambda-1a (Lambda).

Methods

Subjects (age 18–75 years, BMI 18–35 kg m–2) were enrolled into one of five renal function groups: normal (n = 12), mild RI (n = 8), moderate RI (n = 8), severe RI (n = 7), end-stage renal disease (ESRD, n = 8) based on estimated glomerular filtration rate (eGFR) calculated using the Modification of Diet in Renal Disease (MDRD) equation. Subjects received a single dose of Lambda (180 µg) subcutaneously on day 1 followed by PK serum sample collections through day 29. Safety, tolerability and immunogenicity data were collected through day 43. PK parameters were estimated and summarized by group. Geometric mean ratios (GMR) and 90% confidence intervals (CIs) were calculated between normal and RI groups.

Results

With decreasing eGFR, Lambda exposure (Cmax, AUC) increased while apparent clearance (CL/F) and apparent volume of distribution (V/F) decreased. Relative to subjects with normal renal function (geometric mean AUC = 99.5 ng ml–1 h), Lambda exposure estimates (AUC) were slightly increased in the mild RI group (geometric mean [90% CI]: 1.20 [0.82, 1.77]) and greater in the moderate (1.95 [1.35, 2.83]), severe RI (1.95 [1.30, 2.93]) and ESRD (1.88 [1.30, 2.73]) groups. Lambda was generally well tolerated.

Conclusions

The results demonstrated that RI reduces the clearance of Lambda and suggests that dose modifications may not be required in patients with mild RI but may be required in patients with moderate to severe RI or ESRD.  相似文献   

17.
AIMS: To determine the relationship between risedronate pharmacokinetics and renal function. METHODS: Risedronate was administered to adult men and women (n=21) with various degrees of renal function (creatinine clearance 15-126 ml min-1 ) as a single oral dose of 30 mg. Serum samples were obtained for 72 h after dosing, and urine samples were collected for 72 h after dosing and then periodically for 6 weeks. Risedronate concentrations were determined using an enzyme-linked immunosorbent assay (ELISA). Risedronate serum concentration-time and urinary excretion rate-time profiles were analysed simultaneously using nonlinear regression. RESULTS: Renal clearance and volume of distribution were linearly related to creatinine clearance (r2=0.854, P<0.001; and r2=0.317, P<0.01, respectively). Decreases in predicted renal clearance and volume of distribution of 82 and 69%, respectively, were observed when creatinine clearance decreased from 120 to 20 ml min-1. A 64% decrease in predicted oral clearance was observed when creatinine clearance decreased from 120 to 20 ml min-1 (P=0.064). Iohexol clearance, a predictor of renal function, produced similar results to those observed with creatinine clearance. Risedronate was well tolerated by the study population. CONCLUSIONS: Risedronate renal clearance was significantly related to a decrease in renal function. There was a consistent reduction in oral clearance with a decrease in creatinine clearance. However, based on the regression analysis, generally no dosage adjustment appears to be necessary for most patients with mild or moderate renal impairment (creatinine clearance >20 ml min-1 ).  相似文献   

18.
目的研究氟吡汀在中国维吾尔族和汉族健康人体内的药动学。方法选择健康维吾尔族和汉族受试者各10人(男女各半),单剂量口服马来酸氟吡汀胶囊100mg,定时采血,用高效液相色谱-荧光检测法测定血浆中氟吡汀的浓度,用DAS2.0软件进行数据处理,用SPSS11.5软件进行统计分析。结果口服马来酸氟吡汀后,维吾尔族和汉族受试者的主要药动学参数Tmax分别为(1.80±0.75)、(1.70±0.79)h,Cmax分别为(1535.44±398.69)、(1078.09±296.74)μg·L-1,AUC0-36分别为(14343.00±3200.5)、(8406.24±1622.5)μg·h·L-1,AUC0-∞分别为(15021.72±3705.88)、(8971.71±1996.53)μg·h·L-1。结论维吾尔族和汉族健康受试者单剂量口服马来酸氟吡汀胶囊后药动学参数的差异有统计学意义。  相似文献   

19.
Aims The aim of this study was to determine the potential impact of age on the pharmacokinetics of temocapril and its pharmacologically active diacid metabolite, temocaprilat, in hypertensive patients.
Methods Male and female patients with mild to moderate essential hypertension (DBP 95–114  mmHg inclusive) were allocated to two age groups: young, ≤40 years; elderly, ≥69 years, ( n =18 per group). In Part I of the study, subjects took a single oral tablet dose of 20  mg temocapril hydrochloride following an overnight fast. In Part II they took seven once daily oral tablet doses of 20  mg temocapril hydrochloride. Pharmacokinetic profiles were determined after the single and the last dose. Trough plasma samples were taken before each dose in Part II. Urine was collected for 24  h following the single and the last dose.
Results Steady state was reached within 1 week in both groups. Statistically significant differences were detected in AUC and AUCss for temocaprilat as well as in CLR for temocapril and temocaprilat, respectively, after a single dose and at steady state. All other pharmacokinetic parameters for temocapril and temocaprilat did not show any significant difference.
Conclusions The pharmacokinetic differences detected in the elderly do not require a dose adjustment per se . Nonetheless, a lower starting dose may be appropriate as elderly hypertensive patients are usually considered to be at an increased risk of first dose hypotension at the onset of treatment with an ACE inhibitor.  相似文献   

20.
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。  相似文献   

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