Pharmacokinetics and pharmacodynamics of the ace inhibitor benazepril hydrochloride in the elderly

Summary The pharmacokinetics and pharmacodynamics of a single oral dose benazepril·HCl 10 mg have been studied in 15 healthy volunteers aged 65 to 80 y. The kinetics of unchanged benazepril and its active metabolite benazeprilat did not differ significantly in males and females, so the combined kinetic data from all 15 elderly subjects were compared with a historical control group of 19–32 year-old healthy men treated in the same way.The disposition of benazepril was not affected by age. The time to maximum plasma concentration, t_max (0.5 h) and elimination half-life (0.6 h) in the elderly were the same as in young subjects. The kinetics of benazeprilat was slightly changed in the elderly; although its t_max (1.5 h) was not affected, C_max and the AUC were 20–40% greater. The elimination half-life of benazeprilat during the first 24 h after doing in the elderly was increased by about 20% to 3.2 h. The renal plasma clearance of benazeprilat (18.1 ml·min^–1) was about 20% smaller than in the young subjects. An average of 18.5% of the dose was recovered as benazeprilat in the 24 h urine from the elderly subjects, which was similar to the recovery in the young subjects. Both benazepril and benazeprilat were highly bound to serum proteins (96 and 95%, respectively).Mean systolic and diastolic blood pressures in the elderly were reduced by a maximum of 37/16 mm Hg at 6 h, in association with a small rise in pulse rate.Treatment was generally well tolerated. Three of the 15 subjects reported clinical adverse experiences judged to be possibly drug related, namely headache, abdominal pain and cold extremities.Summary results were reported in the Proceedings of a Sattelite Symposium of the X^th Congress of the European Society of Cardiology, 1988, Vienna, Austria [1].     

Pharmacokinetic interaction study between benazepril and amlodipine in healthy subjects

Pharmacokinetic interaction between benazepril (ACE inhibitor) and amlodipine (calcium channel blocker) was studied in 12 healthy subjects. Single doses of benazepril hydrochloride (10-mg tablet) and amlodipine besylate (tablet equivalent to 5 mg amlodipine) were administered alone or in combination according to a three-way, Latin-Square, randomized crossover design. Serial blood samples were collected following each administration for the determination of benazepril and its active metabolite benazeprilat and amlodipine. The mean values of AUC (0–4 h), C_max andT _max for benazepril given as combination versus given alone were 161 vs 140 ng·h·ml⁻¹, 168 vs 149 ng·ml⁻¹, and 0.5 vs 0.6 h. The mean values of AUC (0–24 h), C_max andT _max for benazeprilat after benazepril given as combination versus given alone were 1470 vs 1410 ng·h·ml⁻¹, 292 vs 257 ng·ml⁻¹, and 1.7 vs 1.5 h. The mean values of AUC (0–144 h), C_max andT _max for amlodipine given as combination versus given alone were 118 vs 114 ng·h·ml⁻¹, 2.5 vs 2.3 ng·ml⁻¹, and 8.3 vs 9.0 h. The differences in these pharmacokinetic parameters between the combination and monotherapy treatments were not statistically significant based on ANOVA. The results of this study indicate that no pharmacokinetic interaction existed between the two drugs.     

阿托伐他汀联合贝那普利治疗高血压合并蛋白尿的疗效观察

目的:探讨阿托伐他汀联合贝那普利对高血压合并蛋白尿的疗效.方法:135例患者依就诊次序分为3组,阿托伐他汀组(阿托伐他汀,20 mg/d),贝那普利组(贝那普利,10 mg/d)以及联合用药组(每天20 mg阿托伐他汀和10 mg贝那普利).各组分别在治疗前,治疗6个月和治疗12个月后检测患者的血压、血脂、血肌酐、24h尿蛋白量、尿酸和ALT等指标.结果:与治疗前相比较,联合用药组治疗后(6个月和12个月)能显著下调患者的血压、血脂、血肌酐、24h尿蛋白量和尿酸(P＜0.05),阿托伐他汀组治疗后能显著下调患者的血脂、血肌酐、24h尿蛋白量和尿酸(P＜0.05),贝那普利组治疗后能显著下调患者的血压、血肌酐、24h尿蛋白量和尿酸(P＜0.05).治疗后,与阿托伐他汀组或贝那普利组相比较,联合用药组患者的血脂,血肌酐和24h尿蛋白量的降幅显著(P＜0.05).结论:阿托伐他汀联合贝那普利治疗高血压合并蛋白尿具有满意的疗效,且使用安全,值得临床推广.     

Single dose and steady state pharmacokinetics and pharmacodynamics of the ACE-inhibitor imidapril in hypertensive patients

Aims To investigate the pharmacokinetic profile of the ACE-inhibitor imidapril in 10 hypertensive patients after a first single dose (10  mg) and after 28 days therapy with imidapril 10  mg once daily.
Methods C _max, t _max, t _1/2 and AUC of imidapril and imidaprilat were obtained. ACE-activity and arterial blood pressure during imidapril were corrected by a preceding placebo-investigation.
Results The AUC of imidapril was 140 (43  s.d.)  ng  ml⁻¹ h after the first dose and 123 (34  s.d.)  ng  ml⁻¹ h at steady state. AUC of the active moiety imidaprilat averaged 211 (101  s.d.)  ng  ml⁻¹ h after the first dose and 240 (55  s.d.)  ng  ml⁻¹ h at the steady state investigation. Maximal ACE-inhibition was 75% after the single dose as well as at steady state. ACE inhibition before drug intake at day 28 (i.e. trough) was 50%. The (placebo-corrected) maximal drop in diastolic blood pressure after imidapril was 22  mmHg after the first dose and 25  mmHg at steady state. Exploratory analysis of imidaprilat plasma concentration vs effect profiles suggests a hyperbolic concentration effect relationship where data of the single dose contribute to the ascending part of an E_max-curve, whereas the plateau around E_max is maintained at steady state.
Conclusions In this group of hypertensive patients, the pharmacokinetic profile and the drop in ACE-activity as well as in blood pressure seen after a single dose of imidapril and at steady state were similar. The initial response to a test dose might therefore predict the response during chronic dosing.     

氯沙坦治疗慢性肾小球肾炎蛋白尿的临床研究

目的研究氯沙坦对慢性肾小球肾炎蛋白尿患者肾脏的保护作用。方法将48例患者血压控制于130/80mmHg以下,稳定1周后随机分为两组:氯沙坦治疗组24例,50mg1次/d,苯那普利组24例,10mg1次/d,疗程12周,观察治疗前后24h尿蛋白、肾功能、血钾的变化及不良反应的发生情况。结果氯沙坦与苯那普利均能显著降低尿蛋白,治疗前后有显著性差异(P<0.05),而两组间无显著性差异(P>0.05);两组血压治疗前后无显著性变化;对肾功能的影响,于第4周结束时两组治疗均无明显改变,但在12周结束时两组均较治疗前存在显著性差异(P<0.05),两组间比较差异无显著性(P>0.05);氯沙坦能明显降低血尿酸,且无干咳、高血钾等不良反应。结论氯沙坦治疗慢性肾小球肾炎安全、有效,具有非降压依赖性降低蛋白尿、保护肾功能的作用。     

Pharmacokinetics and pharmacodynamics of a novel orally active angiotensin converting enzyme inhibitor (HOE 498) in healthy subjects

Summary The pharmacokinetics and pharmacodynamics of the angiotensin converting enzyme inhibitor HOE 498 were investigated in 10 healthy normotensive male subjects. Serum levels of the active metabolite M 1 (dicarboxylic acid) of HOE 498 were measured by HPLC up to 14 days after a single oral dose of 10 m g HOE 498. Peak serum concentration of M 1 between 5–50 ng/ml was observed 1.5–3.0 h after administration. The serum concentration-time curve of M 1 was polyphasic and exhibited a prolonged terminal phase with a half-life of approximately 110 h. Despite the long terminal half-life M 1 could not be detected in urine later than 72 h after administration. The activity of the angiotensin converting enzyme in plasma was completely suppressed for up to 12 h, and 72 h after dosing 50% inhibition of the enzyme was still observed.     

Pharmacokinetics and pharmacodynamics of lisinopril in advanced renal failure

To prevent drug accumulation and adverse effects the dose of hydrophilic angiotensin-converting enzyme (ACE) inhibitors, e. g. lisinopril, must be reduced in patients with renal failure. To obtain a rational basis for dose recommendations, we undertook a prospective clinical trial. After 15 days of lisinopril treatment pharmacokinetic and pharmacodynamic parameters were determined in patients with advanced renal failure (n=8; endogenous creatinine clearance [CL_CR]: 18 ml·min^?1·1.73m^?2) and in healthy subjects with normal renal function (n=16; CL_CR: 107 ml·min^?1·1.73m^?2). The volunteers received 10 mg lisinopril once daily, the daily dose in patients (1.1–2.2 mg) was adjusted to the individual CL_CR according to the method of Dettli [13]. After 15 days of lisinopril treatment the mean maximal serum concentration (C _max) in patients was lower than in volunteers (30.7 vs 40.7 ng·ml^?1, while the mean area under the concentration-time curve (AUC _{0–24 h}) was higher (525 vs 473 ng·h^?1·ml^?1). ACE activity on day 15 was almost completely inhibited in both groups. Plasma renin activity, angiotensin I and angiotensin II levels documented marked inhibition of converting enzyme in volunteers and patients. Furthermore, average mean arterial blood pressure in patients decreased by 5 mmHg and proteinuria from 3.9–2.7 g per 24 h after 15 days of treatment with the reduced dose of lisinopril. Adjustment of the dose of lisinopril prevents significant accumulation of the drug in patients with advanced renal failure during chronic therapy. Mean serum levels did not exceed this in subjects with normal renal function receiving a standard dose. Despite substantial dose reduction, blood pressure and proteinuria decreases were observed.     

短期合用缬沙坦与盐酸贝那普利对高血压患者药代动力学与药效学的影响

目的探讨短期合用缬沙坦与盐酸贝那普利（抗高血压药）的药代动力学与药效学.方法16例原发性高血压病人分为缬沙坦单用组和联合用药组,单用组口服缬沙坦每天80 mg,合用组口服缬沙坦每天80 mg、盐酸贝那普利每天10 mg,2组均连服7天;测定服药第7天缬沙坦血药浓度;观察服药前后24 h动态血压、肾素-血管紧张素-醛固酮系统（RAAS）各组分、肾功能及血钾变化.结果主要药代动力学参数Cmax,tmax,t1/2,AUC 2组比较均无统计学差异;服药后,降压幅度合用组显著优于单用组;短期服药后,2组RAAS系统各组分变化均无统计学意义;服药后,肾功能及血钾单用组无显著变化,合用组血钾显著降低,但变化在临床正常范围内.结论短期合用盐酸贝那普利对缬沙坦药代动力学参数无显著影响;合用降压作用起效快,降压幅度优于单用缬沙坦,且较安全.     

Pharmacokinetics of temocapril and temocaprilat after 14 once daily oral doses of temocapril in hypertensive patients with varying degrees of renal impairment

Aims The aim of this study was to determine the potential influence of renal impairment on the pharmacokinetics of temocapril and its pharmacologically active diacid metabolite, temocaprilat. Methods Non-compartmental pharmacokinetics were assessed in four groups of hypertensive patients (n=8 per group, four investigational centres) with normal (creatinine clearance determined via 24 h urine sampling, CL_CR, ≥60 ml min⁻¹ ) and impaired renal function (CL_CR 40–59, 20–39, <20 ml min⁻¹ ) after 14 once daily oral doses of 10 mg temocapril hydrochloride. Results For temocapril, there were no statistically significant differences in median t_max or mean C_max, AUC_SS, t_½,Z, CL/F between the four groups. Renal clearance, CL_R, for temocapril showed a linear decreasing trend with decreasing CL_CR [ mean (s.d.): 32.2 (10.7) to 3.7 (3.0) ml min⁻¹]. Steady-state for temocaprilat was reached on day 5. For temocaprilat, no statistically significant differences in mean C_max or median t_max were detected. With decreasing mean CL_CR, mean AUC_SS for temocaprilat increased statistically significantly although only 2.4-fold [mean (s.d.): 2115 (565) to 4989 (2338) ng ml⁻¹ h] and t_½,Z was prolonged [mean (s.d.): 15.2 (1.2) to 20.0 (7.5) h]. CL_R for temocaprilat showed a linear decreasing trend with decreasing CL_CR [mean (s.d.): 20.2 (4.3) to 3.0 (1.8) ml min⁻¹]. Conclusions These results indicate that impaired renal function has only a limited effect on the pharmacokinetics of temocapril and its active metabolite, temocaprilat. This may be attributed to the dual, i.e. renal and biliary, elimination pathway of the drug.     

硝苯地平控释片与盐酸贝那普利治疗血液透析高血压患者的疗效观察

目的观察硝苯地平控释片（拜新同）及盐酸贝那普利（洛丁新）在血液透析高血压患者中的治疗效果。方法选取2010年1月～2011年12月在本院诊治的68例常规血液透析伴有高血压的患者,随机分为硝苯地平控释片组和盐酸贝那普利组,硝苯地平控释片组36例予以口服硝苯地平控释片治疗高血压（30mg／d,1d2次）,持续4周;盐酸贝那普利组32例予以口服盐酸贝那普利治疗高血压（10mg/d,1d2次）,持续4周,观察并记录两组患者的治疗效果,运用统计学对治疗效果进行统计分析。结果硝苯地平控释片组患者总有效率为94．4％,盐酸贝那普利组患者总有效率为75．0％,硝苯地平控释片组降压效果明显优于盐酸贝那普利组,差异具有统计学意义（P〈0．01）。结论在血液透析伴有高血压患者的治疗方面,硝苯地平控释片的治疗效果明显优于盐酸贝那普利。     

贝那普利在慢性肾小球肾炎患者体内的药动学

目的:探讨贝那普利在慢性肾小球肾炎患者体内药动学的变化。方法:30例慢性肾小球肾炎患者口服20 mg贝那普利后,采用高效液相色谱-串联质谱法(HPLC-MS/MS)检测受试者血浆中内那普利和其代谢物依那普利拉的浓度,并计算主要药动学参数。结果:慢性肾小球肾炎患者贝那普利主要药动学参数血药浓度-时间曲线下面积(AUC0-t)为(72.9±30.5)μg.h.L-1,AUC0-∞为(80.9±12.8)μg.h.L-1,最大血药浓度为(75.8±1.6)μg.L-1,达峰时间为(0.81±0.12)h。贝那普利拉:AUC0-t为(358.3±81.2)μg.h.L-1,AUC0-∞为(402.2±23.4)μg.h.L-1,Cmax为(48.5±7.7)μg.L-1,tmax为(2.01±0.45)h。结论:本实验为贝那普利治疗慢性肾小球肾炎患者临床用药具有重要的指导意义。     

Pharmacokinetics and pharmacodynamics of famotidine in patients with reflux oesophagitis

Summary The pharmacokinetics, pharmacodynamic effect and clinical efficacy of famotidine were studied in 10 patients with reflux oesophagitis Grades I and II. For the pharmacokinetic studies the patients received 20 mg famotidine i. v.The half-life of famotidine was 3.8 h, the total plasma clearance was 297 ml·min^–1, and a steady state volume of distribution of 1.21·kg^–1 was found. For pharmacodynamic assessment, intraoesophageal pH-metry was performed without and after acute treatment with famotidine 20 mg i. v. and following 3 weeks of oral famotidine 80 mg b. d. The resultant percentage total acid exposure time (pH<4 within 24 h) were 23.9%, 19.0% and 19.2% (median), respectively (NS). At the end of 6 weeks of oral therapy, symptomatic and endoscopic improvement had occurred in 9 and 5 patients, respectively.Our study shows that the pharmacokinetics of famotidine in patients with reflux oesophagitis is comparable to that in healthy volunteers and peptic ulcer patients. The clinical response to the treatment appeared comparable to that found after other H₂-receptor antagonists.     

Pharmacokinetics and pharmacodynamics of thiazinamium in asthmatic patients

Summary The pharmacokinetics and pharmacodynamics of thiazinamium (Multergan) were studied after intravenous and intramuscular administration to 7 males with chronic reversible airways obstruction.Disposition after i.v. administration was described by a clearance of 0.54 l·min^–1, central compartment volume of 14.8 l, distribution rate constant 0.092 min^–1, and an elimination rate constant of 0.0044 min^–1. The corresponding estimates after i.m. administration were 0.324 l·min^–1, 34.1 l, 0.035 min^–1, and 0.0018 min^–1. The bronchodilator response (expressed as % predicted FEV1) after i.v. administration was characterized by maximum increase in FEV1 of 33.9%, with an EC₅₀ of 12.8 ng·ml^–1 and an equilibration half-time of 11 min. Corresponding parameter estimates after i.m. administration were 32.2%, 18.8 ng·ml^–1, and 9 min.Anticholinergic activity, measured by the change in heart rate after i.v. administration, showed maximum increase of 76 beats·min^–1, with an EC₅₀ of 176 ng·ml^–1 and an equilibration half-time of 1.3 min. After i.m. administration the corresponding values were 120 beats·min^–1, 250 ng·ml^–1, and 3 min.The optimal plasma concentration of thiazinamium was about 100 ng·ml^–1, which should give a near maximal bronchodilator response (over 80% of predicted normal) and a heart rate of about 100 beats·min^–1.     

依那普利在大鼠体内的药动学研究

目的通过LC-MS/MS法测定大鼠血浆中依那普利活性代谢产物依那普利拉浓度,研究依那普利在大鼠体内的药动学。方法 Wistar大鼠ig依那普利15 mg/kg,采用固相萃取法对大鼠血浆样品预处理,洗脱液为甲醇、水。色谱与质谱条件为Diamond C_(18)色谱柱(150 mm×4.6 mm,5μm);流动相:乙腈–5 mmol/L乙酸铵(45∶55);体积流量:0.5 mL/min;柱温:30℃;进样量:5μL。采用ESI(+)离子源;干燥气(N_2)体积流量11.0 L/min,压力275.8 k Pa,温度350℃;毛细管电压3 500 V;多级反应监测(MRM)模式,正离子模式;EMV为400 e V。结果血浆中内源性物质对测定无干扰,依那普利拉的线性范围为20~1 500 ng/mL,最低定量限为20 ng/mL。准确度和精密度良好。血浆样本中依那普利拉的提取回收率大于85%,且无浓度相关性。经2次冻融以及冷冻14 d稳定良好。大鼠体内依那普利拉的主要药动学参数:AUC_(0-t)为(8015±297.7)ng/mL·h,C_(max)为(1 405±269.10)ng/mL,t_(max)为(2.45±0.19)h,t_(1/2)为(4.82±0.32)h,Clz/F为(2.18±0.10)L/kg·h,Vz/F为(12.63±1.31)L/kg。结论本方法专属性强、灵敏度高、准确性好。通过测定代谢产物依那普利拉经时血药浓度,可以考察依那普利的药动学特征。     

The pharmacokinetics and pharmacodynamics of fosinopril in haemodialysis patients

Summary The pharmacokinetics and pharmacodynamics of fosinoprilat, the diacid of fosinopril sodium (a new angiotensin-converting enzyme (ACE) inhibitor), were investigated in six haemodialysis patients. Intravenous ¹⁴C-fosinoprilat (7.5 mg), oral ¹⁴C-fosinopril sodium (10 mg) and oral fosinopril sodium (10 mg) were administered in an open-label, randomized study.Mean maximum concentration (C_max), clearance (CL), volume of distribution at steady-state (V_ss), mean residence time (MRT_iv), and t_1/2 values after IV administration of ¹⁴C-fosinoprilat were 2,042 g·ml^–1, 11.3 ml·min^–1, 11.01, 16.3 h and 28.3 h, respectively. Following oral administration of ¹⁴C-fosinopril, mean C_max, time to maximum plasma concentration (t_max), and fosinoprilat bioavailability values were 197 ng·ml^–1, 5.2 h and 29.2 %. Para-hydroxy fosinoprilat and fosinoprilat glucuronide comprised approximately 15 % and 2 % of radioactivity recovered in faeces. Four hours of haemodialysis only cleared approximately 1.5 % of the administered dose. The maximum effect (E_max) model was fitted to the percentage inhibition of serum ACE activity vs. fosinoprilat concentration data in three patients. E_max ranged from 95.3 to 102.5 %, and IC₅₀ (the fosinoprilat concentration required to produce 50 % of E_max) ranged from 2.6 to 4.2 ng·ml^–1.Pharmacokinetic variables of the patients were similar to those in patients with moderate to severe renal dysfunction. Dosage modifications or supplemental dosing following dialysis are unnecessary.Presented in part at the Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, San Antonio, TX, March, 1990     

Pharmacokinetics and pharmacodynamics of benazepril in hypertensive patients with normal and impaired renal function.

The pharmacokinetics and pharmacodynamics of benazepril, an angiotensin converting enzyme (ACE) inhibitor, were investigated after administration of a single oral 5-mg dose and 7 more doses on consecutive days to hypertensive patients with normal renal function (NRF) and those with impaired renal function (IRF). The antihypertensive effect of benazepril was observed as early as 30 min after a single dose, and those effects during consecutive dosing were also sustained for 24 h with a lesser diurnal variation in blood pressure (BP). The time to peak (Tmax) and the apparent elimination half-life (t1/2) for benazepril were 0.6-0.7 h and 0.4-0.8 h, respectively. Tmax for its diacid was 1.5-2.4 h in both groups. The area under the plasma concentration-time curve to 24 h (AUC0-24h) for the diacid was significantly greater in the IRF group than in the NRF group. After consecutive dosing of benazepril, AUC0-24h and plasma peak level (Cmax) were significantly increased in the IRF group. Serum ACE activity was markedly suppressed for 24 h after administration, and the inhibition was closely related to plasma diacid levels. A significant inverse correlation was observed between creatinine clearance and the AUC for the diacid. These results suggest that benazepril is rapidly bioactivated to diacid and exhibits rapid onset and long-lasting antihypertensive effects. Dosage reduction might be required to minimize unnecessary drug accumulation in patients with severe IRF.     

Pharmacokinetics and pharmacodynamics of azosemide

Azosemide is used in the treatment of oedematous states and hypertension. The exact mechanism of action is not fully understood, but it mainly acts on both the medullary and cortical segments of the thick ascending limb of the loop of Henle. Delayed tolerance was demonstrated in humans by homeostatic mechanisms (principally an increase in aldosterone secretion and perhaps also an increase in the reabsorption of solute in the proximal tubule). After oral administration to healthy humans in the fasting state, the plasma concentration of azosemide reached its peak at 3-4 h with an absorption lag time of approximately 1 h and a terminal half-life of 2-3 h. The estimated extent of absolute oral bioavailability in humans was approximately 20.4%. After oral administration of the same dose of azosemide and furosemide, the diuretic effect was similar between the two drugs, but after intravenous administration, the effect of azosemide was 5.5-8 times greater than that in furosemide. This could be due to the considerable first-pass effect of azosemide. The protein binding to 4% human serum albumin was greater than 95% at azosemide concentrations ranging from 10 to 100 microg/ml using an equilibrium dialysis technique. The poor affinity of human tissues to azosemide was supported by the relatively small value of the apparent post-pseudodistribution volume of distribution (Vdbeta), 0.262 l/kg. Eleven metabolites (including degraded products) of azosemide including M1, glucuronide conjugates of both M1 and azosemide, thiophenemethanol, thiophencarboxylic acid and its glycine conjugate were obtained in rats. Only azosemide and its glucuronide were detected in humans. In humans, total body clearance, renal clearance and terminal half-life of azosemide were 112 ml/min, 41.6 ml/min and 2.03 h, respectively. Azosemide is actively secreted in the renal proximal tubule possibly via nonspecific organic acid secretory pathway in humans. Thus, the amount of azosemide that reaches its site of action could be significantly modified by changes in the capacity of this transport system. This capacity, in turn, could be predictably changed in disease states, resulting in decreased delivery of the diuretic to the transport site, as well as in the presence of other organic acids such as nonsteroidal anti-inflammatory drugs which could compete for active transport of azosemide. The urinary excretion rate of azosemide could be correlated well to its diuretic effects since the receptors are located in the loop of Henle. The diuretic effects of azosemide were dependent on the rate and composition of fluid replacement in rabbits; therefore, this factor should be considered in the evaluation of bioequivalence assessment.     

Pharmacokinetics and pharmacodynamics of propranolol stereoisomers in hyperthyroid patients

Summary The disposition of propranolol stereoisomers after administration of a single oral dose of the racemic drug was investigated in seven hyperthyroid patients before and after antithyroid drug therapy. The possibility of hypersensitivity to propranolol in the patients was evaluated by constructing plasma propranolol concentration — beta-blocking effect curves. There was no statistically significant difference in elimination half-life (t_1/2) between (±)- and (−)-propranolol before and after antithyroid drug therapy. However, the plasma clearance ( ) of (−)-propranolol was smaller than that of (±)-propranolol, and the difference was statistically significant after antithyroid drug therapy. Decreased was observed in 3 aged hyperthyroid patients compared to the value after antithyroid drug therapy. decreased or did not change in young patients after therapy. No significant difference was observed in the relationship between the tilt-induced pulse rate response and plasma propranolol concentration when treated patients became euthyroid compared to their response in the hyperthyroid state.     

Pharmacokinetics and haemodynamic effects of a single oral dose of the novel ACE inhibitor spirapril in patients with chronic liver disease

Summary The pharmacokinetics and haemodynamic effects of orally administered spirapril, a novel angiotensinconverting enzyme (ACE) inhibitor, have been investigated in patients with liver cirrhosis (n=10), in patients with chronic, non-cirrhotic liver disease (n=8) and in a control group of healthy subjects (n=16).The absorption and elimination of spirapril did not differ between patients with liver disease and control subjects. In contrast, the bioavailability of spiraprilat, the metabolite responsible for the pharmacological action of spirapril, was significantly reduced in patients (AUC 820 g·h·l^–1, 923 g·h·l^–1 and 1300 g·h·l^–1 in patients with cirrhosis, patients with non-cirrhotic liver disease and in healthy subjects, respectively.Compared to healthy subjects, cirrhotic patients had a reduced rate constant of spiraprilat formation (1.10 h^–1 in patients vs. 2.00 h^–1 in control subjects) while the elimination half-life of spiraprilat was not different. The effect of spirapril on diastolic blood pressure was decreased in patients with chronic liver disease as compared to the controls.Thus, the pharmacokinetics of spirapril was unchanged in patients with different types of liver disease, including cirrhosis. However, the bioavailability of spiraprilat and hypotensive effect of spirapril were reduced in patients.