Lack of effect of eprosartan on the single dose pharmacokinetics of orally administered digoxin in healthy male volunteers

Aims To study the effect of eprosartan, a nonbiphenyl tetrazole angiotensin II receptor antagonist, on digoxin pharmacokinetics in a randomized, open-label, two period, period balanced crossover study in 12 healthy men.
Methods Each subject received a single 0.6  mg oral dose of digoxin (Lanoxicaps^® 0.2  mg/capsule, Glaxo Wellcome) alone or following 4 days of dosing with eprosartan 200  mg orally every 12  h. Each study period was separated by a 14 day washout interval. Serial blood samples were obtained for up to 96  h after each digoxin dose for determination of digoxin pharmacokinetics. The effect of eprosartan on digoxin pharmacokinetics was assessed through an equivalence-type approach using AUC(0, t ') as the primary endpoint.
Results For AUC(0, t '), the ratio of digoxin+eprosartan:digoxin alone was 0.99 with a 90% confidence interval (CI) of [ 0.90, 1.09]. For C _max, the ratio was 1.00 with a 90% CI of [0.86, 1.17]. t _max was similar for both regimens. Both regimens were safe and well tolerated.
Conclusions Based on AUC and C _max data, it can be concluded that eprosartan has no effect on the pharmacokinetics of a single oral dose of digoxin.     

Pharmacokinetics of intravenously and orally administered eprosartan in healthy males: absolute bioavailability and effect of food

Eighteen healthy males received a single 300 mg oral dose of eprosartan as the commercial wet granulation formulation under fasting conditions and following a high-fat breakfast and a single 20 mg intravenous (i.v.) dose. The pharmacokinetics of i.v. eprosartan (mean±S.D.) were characterized by a low systemic plasma clearance (131.8±36.2 mL min⁻¹) and a small steady-state volume of distribution (12.6±2.6 L). Oral bioavailability averaged 13.1%, due to incomplete absorption. In vitro dynamic flow cell dissolution data showed that pH-dependent aqueous solubility of eprosartan is one factor which limits absorption. Eprosartan terminal half-life was shorter after i.v. (approximately 2 h) versus oral (approximately 5–7 h) administration, which may be due to detection of an additional elimination phase or absorption rate-limited elimination following oral administration. Oral administration of eprosartan following a high-fat meal compared with fasting conditions resulted in a similar extent of absorption (based on AUC), but a decreased absorption rate. C_max was approximately 25% lower, and a median delay of 1.25 h in time to C_max was observed when eprosartan was administered with food. These minor changes in exposure are unlikely to be of clinical consequence; therefore, eprosartan may be administered without regard to meal times. © 1998 John Wiley & Sons, Ltd.     

Pharmacology of the angiotensin II receptor antagonist,eprosartan

The non-peptide angiotensin II receptor antagonists represent a new class of drugs with demonstrated efficacy in the treatment of hypertension. Eprosartan is a potent, orally active AT₁ receptor antagonist which is chemically distinct from losartan and other non-peptide angiotensin II receptor antagonists. Eprosartan has a high affinity for the angiotensin II AT₁ receptor, but does not interact with the AT₂ receptor, adrenergic receptors or other receptors involved in cardiovascular regulation. In contrast to most other angiotensin II antagonists, eprosartan is a true competitive antagonist of the AT₁ receptor. Eprosartan is effective in antagonising the cardiovascular and renal effects of exogenous angiotensin II in both experimental animals and humans. Furthermore, it is an effective antihypertensive agent when administered to renin-dependent hypertension animal models, and in patients with mild to severe hypertension. The antihypertensive effect of eprosartan is maintained over a 24-h interval following a single dose with no reported dose-dependent adverse side-effects.     

The effects of age and gender on the pharmacokinetics of irbesartan

Aims Single dose pharmacokinetics and safety of irbesartan, an angiotensin II receptor antagonist, were evaluated in healthy young and elderly male and female subjects.
Methods Irbesartan was administered as two 25  mg capsules after a 10  h fast to 12 young men, 12 young women, 12 elderly men and 12 elderly women. Serial blood and urine sample were collected up to 96  h after the dose. Plasma and urine samples were analysed for irbesartan by h.p.l.c./fluorescence methods.
Results No statistically significant gender effects were observed in peak plasma concentration ( C _max ), area under the curve (AUC), and terminal elimination half-life ( t _1/2 ) of irbesartan. The geometric mean AUC and C _max increased by about 43% and 49%, respectively, in the elderly subjects. Also the time to peak was significantly shorter in the elderly subjects compared with that observed in the young subjects. Renal clearance of irbesartan was significantly reduced in the elderly females but this reduction is not likely to be of any clinical relevance since less than 3% of the administered dose of irbesartan is excreted unchanged in the urine.
Conclusions Although there was an effect of age on the pharmacokinetics of irbesartan, based on the safety and efficacy profile, no adjustment in irbesartan dosage is necessary with respect to age or gender.     

The effects of age and gender on the pharmacokinetics and pharmacodynamics in healthy subjects of the plasminogen activator, lanoteplase

AIMS

To investigate the influence of age and gender on the intravenous pharmacokinetics and pharmacodynamics of the plasminogen activator, lanoteplase.

METHODS

Forty healthy subjects (10 each of young males, elderly males, young females and elderly females) received a single bolus 10 kU kg⁻¹ intravenous dose of lanoteplase. Plasma from blood serially collected for 24 h post-dose was analyzed for lanoteplase (antigen), fibrinogen, plasminogen and α₂-antiplasmin concentrations, plasma plasminogen activation activity (PPAA) and rapid plasminogen activator inhibitor (PAI-1).

RESULTS

Lanoteplase mean total systemic clearance (CL_t) values ranged from 1.9 to 2.8 l h⁻¹ and mean steady-state volume of distribution (V_ss) values ranged from 12.3 to 15.6 l. Age-by-gender interactions were observed for lanoteplase CL_t (P = 0.04), but no differences were observed for V_ss or elimination half-life. Elderly females had a 27% lower mean CL_t than young females (95% CI for the difference 0.17, 1.27 l h⁻¹) and 32% lower CL_t than elderly males (95% CI for the difference 0.15, 1.65 l h⁻¹). PPAA AUC/dose values did not show an age-by-gender interaction. Haemostasis parameters indicated only a slight degree of systemic plasminogen activation.

CONCLUSIONS

Elderly females had a lower mean lanoteplase CL_t than elderly males and young females. However, no difference was observed between young and elderly females for the AUC/dose of PPAA. In addition, there were no age-related or gender-related differences observed in the other pharmacodynamic parameters measured.     

The effect of age, gender, and body mass index on the pharmacokinetics and pharmacodynamics of vildagliptin in healthy volunteers

Aims

To evaluate the effect of age, gender, and body mass index (BMI) on the pharmacokinetics and pharmacodynamics of vildagliptin.

Methods

Forty healthy subjects received a single oral dose of 100 mg vildagliptin to assess the effects of age, gender, and BMI on the pharmacokinetics and pharmacodynamics, reflected by the time course of inhibition of DPP-4 activity, of vildagliptin.

Results

Peak concentration and exposure (AUC_(0–∞)) of vildagliptin were 17% (90% CI 2, 35%) and 31% (90% CI 18, 45%) higher in elderly vs. young subjects. Renal clearance was reduced by 32% (90% CI 17, 45%) in elderly subjects. The pharmacokinetics of vildagliptin were not significantly influenced by gender or BMI. Inhibition of DPP-4 activity was similar regardless of age, gender, or BMI.

Conclusions

The pharmacokinetics of a single oral 100 mg dose of vildagliptin were not affected by gender and BMI. Exposure to vildagliptin was higher in elderly patients, but this was not associated with any difference in the effect of DPP-4 inhibition. Based on these results, no vildagliptin dose adjustment is necessary for age, gender, or BMI.

What is already known about this subject

• Vildagliptin is a new, potent, and selective inhibitor of DPP-4.
• The efficacy and safety of vildagliptin in type 2 diabetes has been intensively studied in diverse subject populations.
• There has been little information published about the pharmacokinetics and pharmacodynamics of vildagliptin.

What this study adds

• No clinically relevant changes in pharmacokinetics or pharmacodynamics were observed between young and elderly, male and female, or high body mass index (BMI) and low BMI subjects.
• The results suggest that no dose modification is necessary for vildagliptin based on the age, gender, or BMI of a subject.

     

依普罗沙坦与氯沙坦在轻中度原发性高血压病人中的降压疗效比较

目的:以氯沙坦为对照,观察依普罗沙坦治疗轻、中度原发性高血压(EH)病人的疗效与安全性。方法:采用前瞻性、随机、双盲、阳性药对照研究。符合方案的50例轻、中度EH病人经筛选期(2 wk)、安慰剂导入期(2 wk)后,随机分为依普罗沙坦组(n=24)与氯沙坦组(n=26)。在治疗期,2组病人分别每日1次口服依普罗沙坦600 mg或氯沙坦50 mg。若4 wk血压不达标,即坐位舒张压(DBP)≥90 mmHg (1 mmHg=0．133 3 kPa),加氢氯噻嗪12．5 mg,每日1次口服至8 wk。观察治疗前、治疗后4 wk与8 wk血压、心率以及治疗前后血、尿常规,血生化及心电图改变。结果:在治疗后8 wk,依普罗沙坦组的收缩压(SBP)与DBP分别下降了(12±s 10)mmHg与(12±5)mmHg,氯沙坦组的降压幅度分别为(14±9)mmHg与(10±6)mmHg,治疗前后比较有非常显著差异(P<0．01);但2组间血压下降的幅度无显著差异(P>0．05)。依普罗沙坦组与氯沙坦组的降压总有效率分别为100％和8l％,2组疗效无显著差异(P>0．05)。依普罗沙坦组加用氢氯噻嗪病例为9例(38％),而氯沙坦组为6例(23％),p> 0．05。2组心率及血液生化检查结果,治疗前后变化均无显著意义(P>0．05),均无严重不良反应发生。结论:依普罗沙坦与氯沙坦均能有效降低轻、中度EH病人的血压,疗效相似,都具有良好的安全性。     

Synthesis and biological evaluation of [carboxyl‐11C]eprosartan

Essential hypertension occurs in approximately 25% of the adult population and one cause of hypertension is primary aldosteronism. Targeting the angiotensin II AT₁ receptor using PET and an appropriate tracer may offer a diagnostic method for adrenocortical tissue. This report describes the synthesis of the selective AT₁ receptor antagonist [carboxyl‐¹¹C]eprosartan 10, 4‐[2‐butyl‐5‐((E)‐2‐carboxy‐3‐thiophen‐2‐yl‐propenyl)‐imidazol‐1‐ylmethyl]‐[carboxyl‐¹¹C]benzoic acid, and its precursor (E)‐3‐[2‐butyl‐3‐(4‐iodo‐benzyl)‐3H‐imidazol‐4‐yl]‐2‐thiophen‐2‐ylmethyl‐acrylic acid 9. ¹¹C‐carboxylation of the iodobenzyl moiety was performed using a palladium‐mediated reaction with [¹¹C]carbon monoxide in the presence of tetra‐n‐butyl‐ammonium hydroxide in a micro‐autoclave using a temperature gradient from 25 to 140°C over 5 min. After purification by semipreparative HPLC, [carboxyl‐¹¹C]eprosartan 10 was obtained in 37–54% decay‐corrected radiochemical yield (from [¹¹C]carbon monoxide) with a radiochemical purity >95% within 35 min of the end of bombardment (EOB). A 5‐µAh bombardment gave 2.04 GBq of 10 (50% rcy from [¹¹C]carbon monoxide) with a specific activity of 160 GBq µmol^?1 at 34 min after EOB. Frozen‐section autoradiography shows specific binding in kidney, lung and adrenal cortex. In vivo experiments in rats demonstrate a high accumulation in kidney, liver and intestinal wall. Copyright © 2009 John Wiley & Sons, Ltd.     

依普沙坦治疗高血压的临床研究进展简

依普沙坦是一种高选择性的血管紧张素Ⅱ-1型（AT1）受体拮抗剂.单次口服后达峰时间（tmax）为1～2.5 h,血浆蛋白质结合率高达98％;多次口服600mg/d,消除半衰期（t12）为20 h,平均稳态分布容积（Vss）为308 L.随机、双盲、多中心临床试验结果表明,依普沙坦的降压效果与依那普利、尼群地平、缬沙坦和替米沙坦相似,对收缩压的降低作用强于氯沙坦;对高血压病人的卒中二级预防作用优于尼群地平,而且依普沙坦对年龄≥50岁的新诊断为高血压的病人,在降压的同时还可适当改善他们的认知功能.病人对依普沙坦的耐受性较好,持续干咳的发生率明显低于依那普利.     

Lack of age and gender effects on single-dose pharmacokinetics of tomopenem (RO4908463/CS-023), a novel carbapenem

AIMS

To investigate the effect of age and gender on the tolerability, safety and pharmacokinetics (PK) of tomopenem (RO4908463/CS-023), a novel carbapenem antibiotic, and its major metabolite.

METHODS

Forty-two subjects were assigned to one of the following three groups: young men, elderly men and elderly women. The PK, safety and tolerability of an intravenous infusion of 1500 mg tomopenem and its resultant major metabolite (open beta-lactam ring) were assessed.

RESULTS

Minor differences in exposure of both tomopenem and the major metabolite were seen. The area under the curve (AUC) of tomopenem was 22% higher in elderly men compared with young men, and 19% higher in elderly women relative to the elderly men. Total clearance of tomopenem decreased with decreasing creatinine clearance. In the two male groups, renal clearance values of tomopenem were similar (3.52 and 3.67 l h⁻¹) and higher than in the elderly female group (2.83 l h⁻¹). The mean half-lives ranged from 2.03 (healthy young men) to 2.41 h (elderly men). The difference in AUC of tomopenem can be explained by differences in the mean creatinine clearances of 116 (young men), 101 (elderly men) and 84.7 (elderly women) ml min⁻¹ 1.73 m⁻², respectively.

CONCLUSIONS

While some PK parameters were statistically different among the three groups, the differences were mostly minor and unlikely to be clinically meaningful. The difference in the PK can be largely attributed to the difference in creatinine clearance of these groups.     

性别对药代动力学的影响

性别对药代动力学的影响越来越受到重视,药代动力学的性别差异是药物作用个体差异的主要因素。了解药代动力学的性别差异有利于提高用药的安全性和有效性。近年来关于药代动力学性别差异的研究取得了较大的进展,本文综述了相关领域的研究结果。     

Lack of gender effect on ciprofloxacin pharmacokinetics in humans

The influence of gender on the single-dose pharmacokinetics of oral ciprofloxacin was investigated in a parallel designed study in 24 healthy, fasted volunteers. Ciprofloxacin (750 mg) was administered as a single tablet to 10 women and 14 men. All subjects were Caucasian except for one African American man. The mean age was 36 years for men and 33 years for women. Women received the drug during the nonmenstruating phase of their menstrual cycle and were not taking oral contraceptives at the time of the study. Plasma samples were collected over a 24 h period and assayed by h.p.l.c. The 90% confidence limits for the ratio of geometric means of maximum plasma concentration, apparent terminal half-life, and apparent oral plasma clearance (corrected for body weight) were between 80% and 125%, and those for the area under the plasma concentration-time curve were 71% and 101%. Results suggest that there were no gender-related differences in ciprofloxacin pharmacokinetics in men and nonmenstruating women of middle age.     

The effect of gender on the pharmacokinetics of verapamil and norverapamil in human

The effects of gender on the pharmacokinetics of verapamil and its active metabolite, norverapamil, following single oral dose (80 mg, Isoptin) to 12 healthy male (mean age: 25.75+/-2.42 years, mean body weight: 70.59+/-9.94 kg) and 12 healthy female subjects (mean age: 24.08+/-2.84 years, mean body weight: 56.67+/-5.23 kg) were investigated in the present study. Plasma concentrations of verapamil and norverapamil were analysed using a modified high-pressure liquid chromatography method. Pharmacokinetic parameters were calculated by non-compartmental analysis for each subject. For verapamil the half-life (t1/2) and mean residence time (MRT) were significantly shorter in women than men (p<0.01 and p<0.05, respectively). For other pharmacokinetic parameters of verapamil there were no significant differences between males and females. For norverapamil, t1/2, MRT and time to reach to the maximum plasma concentration (Tmax) showed statistically significant differences between the two genders. The AUC(0-24) and AUC(0-infinity) ratios of norverapamil to verapamil were also calculated. The ratios were significantly higher in women compared with men. These observations indicate that the elimination rate of verapamil is faster in women than men which may be attributed to the higher activity of CYP3A4 or lower activity of P-glycoprotein in women compared with men. A contribution of both factors in the appearance of gender differences in verapamil pharmacokinetics is also possible.     

与性别因素相关的莫达非尼药动学特征的Meta分析

摘要目的：评价莫达非尼在人体内药动学特征是否具有性别差异,制定合理的临床给药方案。方法：检索Pubmed、Medline、Ovid、springerlink、CNKI、VIP、CBM等数据库,选取自1994年1月至2013年2月间发表的有关莫达非尼（单剂量口服给药）在人体内药动学研究方面的文献,按系统评价方法进行筛选,用Revman5．0软件对药物消除半衰期（≠。棚）、曲线下面积（AUC0-∞）和血药浓度达峰时间（tmax）三个药动学参数进行Meta分析。结果：共纳入8篇文献,含样本207例。Meta分析结果显示,与男性相比,女性的t1／2β明显缩短（均数差为1．13,95％CI=0．31～1．96,P=0．007）,AUC0-∞则显著增大（均数差为一6．37,95％CI=一9．20～一3．53,P〈0．0001）;而tmax无明显性别差异（均数差为一0．11,95％CI=0．32～0．10。P=0．32）。结论：莫达非尼在人体内的t1/2β与AUC0-∞等药动学参数存在性别差异,这为制定合理的临床给药方案提供了药动学参考。     

缬沙坦治疗慢性心力衰竭的临床疗效观察

目的:探讨缬沙坦治疗慢性心力衰竭的疗效和安全性.方法:选择冠心病缺血性心肌病、扩张型心肌病、高血压性心脏病、风湿性心脏病慢性心衰患者26例,在使用常规利尿剂、血管扩张剂、强心剂等治疗的基础上,加用血管紧张素Ⅱ受体拮抗剂缬沙坦口服,采用自身对照观察比较用药前、治疗后8周心脏指标变化,评估临床有效性及安全性.结果:治疗8周后显效8例,有效14例,总有效率88%,无效3例,占12%.结论:在常规治疗的基础上,加用缬沙坦治疗慢性心力衰竭效果显著,可改善心功能及临床症状,提高患者的生活质量.     

Human pharmacokinetics of nitrazepam: Effect of age and diseases

Summary Plasma concentrations of nitrazepam were measured by gas-liquid chromatography in: young healthy volunteers, in geriatric and psychiatric patients and in epileptic children. The disposition of nitrazepam was described in terms of a two-compartment open model. After a single oral dose of nitrazepam 5 mg the most prominent differences between the experimental groups were in the -phase half-life-mean 29 h in the young volunteers and 40 h in geriatric patients, and in the apparent volume of distribution during the -phase of 2.4 vs 4.8 l/kg. Total plasma clearance and the average steady state concentration in both groups were equal. The plasma level rose at a rate proportional to the -phase half-life, and so, they were achieved more rapidly in the young than in the old subjects (3.5 vs 7.5 d). No change in steady-state level or in the half-life of nitrazepam were found during long term treatment, which indicates lack of enzyme induction or inhibition. In 95% of the epileptic children with a good to fair clinical response, the plasma concentration of nitrazepam was 40–180 ng/ml (mean 114 ng/ml). As all of the patients were on combined antiepileptic therapy, no attempt was made to correlate plasma level with therapeutic response.Supported by Orion Foundation, Helsinki, Finland     

Gentamicin pharmacokinetics in old age and frailty

AIMS

Frailty, a syndrome of decreased physiological reserve that is prevalent in old age, impacts on clinical pharmacology. The aims of the study were to (1) determine whether frailty affects the pharmacokinetics of gentamicin and (2) assess the accuracy of different estimates of body size and renal clearance as estimates of gentamicin pharmacokinetics in older inpatients.

METHODS

This was an observational study of gentamicin pharmacokinetics in a cohort of Australian hospital inpatients aged ≥65 years, who were administered prophylactic intravenous gentamicin.

RESULTS

Of the 31 participants, 14 were frail and 17 non frail on the Reported Edmonton Frail Scale. The mean volume of distribution of gentamicin was 14.8 ± 1.4 l in frail participants and 15.3 ± 2.2 l in non frail (NS). Volume of distribution correlated best with lean bodyweight. Gentamicin clearance was significantly lower in frail participants (46.6 ± 10.7 ml min⁻¹) than in non frail (58.2 ± 12.4 ml min⁻¹, P= 0.01). The Cockcroft Gault estimate of creatinine clearance calculated using ideal bodyweight gave the best estimate of gentamicin clearance (mean error – 0.15 ml min⁻¹, 95% CI −2.67, 2.39). The Cockcroft Gault creatinine clearance calculated using actual bodyweight and the estimated glomerular filtration rate from the modified diet in renal disease equation overestimated gentamicin clearance, with mean errors of −10.15 ml min⁻¹ (95%CI −13.60, −6.71) and −18.86 ml min⁻¹ (95% CI −22.45, −15.27), respectively. The Cockcroft Gault creatinine clearance calculated using lean bodyweight underestimated gentamicin clearance (mean error 6.54 ml min⁻¹, 95% CI 4.18, 8.90).

CONCLUSIONS

Frail older people have significantly lower gentamicin clearance than non frail. The best estimate of gentamicin clearance is obtained from the Cockcroft Gault creatinine clearance calculated using ideal bodyweight.     

氯沙坦治疗原发性高血压并高尿酸血症

目的:观察氯沙坦治疗原发性高血压并高尿酸血症的降压和降尿酸作用.方法:68例原发性高血压并高尿酸血症患者,随机分为治疗组与对照组,观察给药前后血压和血尿酸变化.结果:两组均降压效果明显,治疗组能明显降低血尿酸,两组差异具有显著性.结论:氯沙坦降压同时可降尿酸.     

血管紧张肽Ⅱ受体拮抗剂的药动学与临床用药

血管紧张肽Ⅱ受体拮抗剂 (ARB)是一类在血管紧张肽Ⅱ 1型受体 (AT1受体 )水平拮抗血管紧张肽Ⅱ (ATⅡ )的降压药物。它们的药动学各具特色 ,因而具有不同的临床用药特点。氯沙坦 (losar tan)经细胞色素P 450 (CYP) 3A4及 2C9介导转化成其活性代谢物EXP31 74,故在肝功能不全时应减半量使用。替米沙坦 (telmisartan)的T1 / 2 最长 ,谷 /峰比最大 ,与地高辛合用时应动态监测地高辛血浓度 ,以免洋地黄中毒。由于ARB存在降压作用的平台反应 ,单一用药无法控制血压时 ,可联合应用利尿剂或钙拮抗剂。本文就ARB的药动学、降压治疗用药、联合用药 ,肝、肾功能不全时用药及药物相互作用作一综述     

Effects of angiotensin II blockade on inflammation-induced alterations of pharmacokinetics and pharmacodynamics of calcium channel blockers

BACKGROUND AND PURPOSE: Inflammation elevates plasma verapamil concentrations but diminishes pharmacological response. Angiotensin II is a pro-inflammatory mediator. We examined the effect of angiotensin II receptor blockade on the pharmacokinetics and pharmacodynamics of verapamil, as well as the binding properties and amounts of its target protein in calcium channels, in a rat model of inflammation. EXPERIMENTAL APPROACH: We used 4 groups of male Sprague-Dawley rats (220-280 g): inflamed-placebo, inflamed-treated, control-placebo and control-treated. Inflammation as pre-adjuvant arthritis was induced by injecting Mycobacterium butyricum on day 0. From day 6 to 12, 30 mg kg(-1) oral valsartan or placebo was administered twice daily. On day 12, a single oral dose of 25 mg kg(-1) verapamil was administered and prolongation of the PR interval measured and plasma samples collected for verapamil and nor-verapamil analysis. The amounts of the target protein Ca(v)1.2 subunit of L-type calcium channels in heart was measured by Western blotting and ligand binding with (3)H-nitrendipine. KEY RESULTS: Inflammation reduced effects of verapamil, although plasma drug concentrations were increased. This was associated with a reduction in ligand binding capacity and amount of the calcium channel target protein in heart extracts. Valsartan significantly reversed the down-regulating effect of inflammation on verapamil's effects on the PR interval, and the lower level of protein binding and the decreased target protein. CONCLUSIONS AND IMPLICATIONS: Reduced responses to calcium channel blockers in inflammatory conditions appeared to be due to a reduced amount of target protein that was reversed by the angiotensin II antagonist, valsartan.