Pharmacokinetics and converting enzyme inhibition after morning and evening administration of oral enalapril to healthy subjects

Summary Possible circadian changes in the pharmacokinetics and effect on serum angiotensin-converting enzyme (ACE) activity of the ACE inhibitor enalapril have been studied in 8 healthy subjects after oral ingestion of 10 mg enalapril maleate either at 08.00 h or 20.00 h. The time to peak serum concentration (t_max) of enalapril was increased after administration at 20.00 h compared to 08.00 h (2.4 h versus 1.3 h), where as other kinetic parameters were not significantly altered. The 24 h-kinetics of the active metabolite enalaprilat did not differ significantly between the two treatments, but the area under the curve (AUC (0–24)) and the peak serum concentration (C_max) were slightly higher after intake at 20.00 h. The relationship between the measured serum enalaprilat level and the degree of inhibition of serum ACE was the same after both treatments. Overall, the evening and morning administration of enalapril did not differ markedly in the pharmacokinetics and the time course of ACE inhibition.This report is part of the thesis to be presented by K. Weisser in partial fulfillment of the requirements for the degree of Doctor of Natural Science.     

Age and the pharmacokinetics of angiotensin converting enzyme inhibitors enalapril and enalaprilat.

The pharmacokinetics of angiotension converting enzyme (ACE) inhibitors enalapril (10 mg orally) and its active metabolite, enalaprilat (10 mg intravenously) were studied in nine young healthy volunteers aged 22-30 years and nine sex matched elderly subjects aged 65-73 years. After both drugs, a biexponential curve was fitted to the decline in plasma enalaprilat concentration. Area under the plasma concentration-time curve (AUC) was greater in the elderly for both drugs. Clearance (CL) and clearance/bioavailability (CL/F) were less in the elderly for enalaprilat and enalapril, respectively. There was no difference in F between young (0.62 +/- 0.16) and elderly subjects (0.61 +/- 0.15). Enalaprilat CL and enalapril CL/F were significantly and positively correlated to endogenous creatinine clearance. There was a significant difference in the weight corrected volume of distribution at steady state after enalaprilat between the young and elderly (P less than 0.02). The relationship between plasma enalaprilat concentrations and percentage ACE inhibition, using the Hill equation, showed no difference in the sensitivity to ACE inhibition between the young and the elderly group. The pharmacokinetic differences observed are likely to be related to an age dependent decline in renal function as well as changes in body composition. Kinetic differences partly explain the greater pharmacodynamic response in the elderly.     

Comparison of the pharmacokinetics of fosinoprilat with enalaprilat and lisinopril in patients with congestive heart failure and chronic renal insufficiency

AIMS: To compare the serum pharmacokinetics of fosinoprilat with enalaprilat and lisinopril after 1 and 10 days of dosing with fosinopril, enalapril and lisinopril. METHODS: Patients with congestive heart failure (CHF, NYHA Class II-IV) and chronic renal insufficiency (creatinine clearance 相似文献   

Pharmacokinetic comparison of a combination tablet of enalapril and hydrochlorothiazide with enalapril and hydrochlorothiazide tablets administered together and separately

Enalapril and hydrochlorothiazide (HCT) are established single agent treatments for mild hypertension and cardiac failure and are a potent combination in more severe or resistant cases. We have compared the pharmacokinetics of enalaprilat (the active metabolite of enalapril) and HCT in a four-way comparison of a combination tablet of enalapril (10 mg)/HCT (25 mg) with a single dose of an enalapril tablet (10 mg), a single dose of a HCT tablet (25 mg) and simultaneous administration of separate tablets of enalapril (10 mg) and HCT (25 mg) in normotensive volunteers (n = 12, 21-26 years). Each subject received all four treatments and the study was conducted as a randomized, latin square, open design with at least 1 week washout between studies. Overall, HCT was bioequivalent under all conditions and enalaprilat was bioequivalent when given in combination with HCT either as one tablet or as two separate tablets. However, when given with HCT, the mean AUC and Cmax of enalaprilat were reduced up to 20 per cent compared with enalapril administered alone. This is unlikely to be of clinical significance as the differences did not reach statistical significance and the total enalaprilat excreted in the urine over 96 h was similar after all treatments.     

The effect of saturation of ACE binding sites on the pharmacokinetics of enalaprilat in man.

1. Eight healthy male volunteers received oral enalapril, 10 mg, in the presence and absence of pretreatment with captopril, 50 mg, twice daily for 5 days. 2. Enalaprilat pharmacokinetics were characterised after both doses of enalapril to investigate the effect of saturating ACE binding sites by pretreatment with captopril. 3. The pharmacokinetics of enalaprilat were best described by a one compartment model with zero order input incorporating saturable binding to plasma and tissue ACE. 4. Values of AUC (0.72 h) for enalaprilat were 419 +/- 97 and 450 +/- 87 ng ml-1 h in the presence and absence of captopril, respectively. The difference was not statistically significant nor were there any other differences in model parameters. 5. Induction of ACE by captopril resulting in an increase in the number of ACE binding sites, may have obscured any effect of captopril on the occupancy of ACE binding sites by enalapril.     

Effect of cimetidine on the pharmacokinetics and pharmacodynamics of enalapril in normal volunteers

The possible effects of cimetidine on the pharmacokinetics and pharmacodynamics of enalapril, a pro-drug requiring hepatic de-esterification to an active angiotensin-converting enzyme (ACE) inhibitor enalaprilat, were assessed in a randomized, crossover study. Cimetidine (400 mg) or placebo was administered orally every 12 h for 3 days and on the day of a single oral administration of enalapril maleate (10 mg) to seven healthy male subjects. Serum ACE, plasma renin activity (PRA), plasma aldosterone concentration (PAC), and alpha-human atrial natriuretic peptide (alpha-hANP) were measured before and 4 h after the enalapril dosing. There were no significant differences in any serum- and urine-derived kinetic parameters of enalapril and enalaprilat, nor in hemodynamics, PAC, or alpha-hANP between the two treatment trials. ACE decreased and PRA increased to a similar extent in the two trials. Serum enalaprilat concentration correlated significantly (p less than 0.001) with percentage of inhibition of ACE activity. The results suggest that the pharmacokinetics and pharmacodynamics of enalapril are unaffected by preadministration of cimetidine. Thus, cimetidine does not appear to alter hepatic esterase activity toward enalapril.     

Pharmacokinetic and pharmacodynamic comparative study of zofenopril and enalapril in healthy volunteers

Zofenopril calcium (CAS 81938-43-4) is a new angiotensin converting enzyme (ACE) inhibitor, which in addition to the typical activity of the class, proved to possess a specific cardioprotective effect due also to the presence of the sulfhydryl group. In this trial zofenopril calcium and enalapril maleate (CAS 76095-16-4) were given to 20 healthy volunteers of both sexes in repeated dose regiment at two dose levels: 30 mg and 60 mg zofenopril calcium and 10 mg and 20 mg enalapril maleate. The study was conducted according to a two-period, two-sequence, crossover design, with washout. ACE activity in serum and zofenopril, zofenoprilat, enalapril and enalaprilat plasma concentrations were determined during and on the last day of the two study periods. Both zofenopril and enalapril were extensively converted through hydrolysis to their active metabolites zofenoprilat and enalaprilat, respectively. Zofenopril exhibited a complete and a more rapid hydrolysis rate compared to enalapril, which is reflected by the higher metabolite to parent drug ratio of Cmax and AUCss, tau showed by this compound. Even though only two dose levels were investigated in this trial, the pharmacokinetics of both drugs seem to be linear. In line with previous trials, both compounds at both dose levels investigated produced complete or almost complete inhibition of ACE activity in serum, for a period lasting 6-8 h after administration, the inhibition being still relevant 24 h thereafter. The tolerability of the two drugs at both dose levels proved to be very good as demonstrated by subjective and objective symptoms, by the absence of relevant adverse events, and by laboratory biochemical parameters and vital signs evaluated before and after the trial. Blood pressure showed a fairly decreasing trend with both the drugs, systolic and diastolic blood pressure values being however within normal range in all the subjects. In no case symptoms of hypotension were experienced. In conclusion, zofenopril calcium and enalapril maleate show very good tolerability and appear to exert similar activity on serum ACE. The main difference in the pharmacokinetics of the two compounds is the conversion from pro-drug to the active metabolite which is faster with zofenopril.     

The pharmacokinetics of enalapril in hospitalized patients with congestive heart failure.

The pharmacokinetics of the converting enzyme inhibitor, enalapril, were studied in an open, randomized, balanced crossover design in 12 hospitalized patients with stable, chronic congestive heart failure (CHF). Enalapril maleate is a prodrug requiring in vivo hepatic esterolysis to yield the active diacid inhibitor enalaprilat. CHF results in changes in regional blood flow that may affect the gastrointestinal absorption, hepatic hydrolysis and renal excretion of enalapril and enalaprilat. In order to evaluate the pharmacokinetics of enalapril in CHF, the following treatments were given: enalapril maleate 10 mg orally, enalapril maleate 5 mg intravenously and enalaprilat 5 mg intravenously. Each dose was followed by a 72 h period with frequent blood sampling and fractionated urine collection for the radioimmunoassay of enalaprilat, before and after sample hydrolysis. Mean absorption for the oral dose was 69%, hydrolysis 55%, bioavailability 38%, urinary recovery 77% and estimated first-pass effect 10%. The results were compared with available data in normal subjects. After oral administration of 10 mg enalapril maleate, the extent of absorption, the degree of hydrolysis and the bioavailability in CHF patients appear to be similar to those in normals with differences less than 10%. The rate of absorption and hydrolysis appear to be slightly slower in CHF. The serum concentrations of enalaprilat were consistently greater in CHF and maximal concentrations were reached at 6 h in CHF as compared to 4 h in normal subjects. We conclude that the presence of CHF does not appreciably alter the pharmacokinetic behaviour of enalapril. The observed differences may be associated with age as well as the disease state.     

Bioequivalence study of two enalapril maleate tablet formulations in healthy male volunteers Pharmacokinetic versus pharmacodynamic approach

Objective: Two different conventional release enalapril maleate tablet formulations were evaluated for their relative bioavailability (Eupressin tablets 10 mg, Biosintética as the test formulation vs Renitec tablets 10 mg Merck Sharp & Dhome, as the reference formulation). A single 20 mg oral dose of each preparation was administered to 18 healthy male adult volunteers and their bioequivalence was assessed by comparing the serum enalaprilat and total enalapril (enalaprilat plus enalapril maleate) concentration-time curves. Angiotensin converting enzyme (ACE) activity was also quantified in each serum sample. Results: The pharmacokinetic parameters obtained for each formulation were the area under the time-concentration curve from 0 to 24 h (AUC_[0–24]), maximum concentration C_max and the time at which it occurred (t_max). When serum enalaprilat concentration-time curves were employed to assess bioequivalence, the formulations were bioequivalent in the extent but not in the rate of absorption. However, no difference in either the extent or the rate of absorption were observed when serum total enalapril vs time curves were analysed. ACE activity-time curves were similar for both formulations and showed that ACE was 90% inhibited 3–5 h after enalapril administration, and till approximately 50% after 24 h. At that time, circulating enalaprilat and total enalapril levels were less than the tenth of C_max. Conclusion: The results show that complete bioequivalence of the two formulations can be concluded from serum total enalapril concentration data, and that serum ACE activity is not a suitable pharmacodynamic variable for assessing bioequivalence. Received: 29 May 1995/Accepted in revised form: 30 October 1995     

Enalapril, a nonsulfhydryl angiotensin-converting enzyme inhibitor

The chemistry, pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage of enalapril maleate, a nonsulfhydryl angiotensin-converting enzyme (ACE) inhibitor, are reviewed. Enalapril is rapidly converted by ester hydrolysis to enalaprilat, a potent ACE inhibitor; enalapril itself is only a weak ACE inhibitor. Enalapril lowers peripheral vascular resistance without causing an increase in heart rate. In patients with congestive heart failure, enalapril has beneficial hemodynamic effects based on reduction of both cardiac preload and afterload. Approximately 60% of a dose of enalapril is absorbed after oral administration. Excretion of enalaprilat is primarily renal. Accumulation of enalaprilat occurs in patients with creatinine clearances less than 30 mL/min. Enalapril 10-40 mg per day orally has shown efficacy comparable to that of captopril in treating patients with mild, moderate, and severe hypertension, hypertension caused by renal-artery stenosis, and in congestive heart failure resistant to digitalis and diuretics. When given alone for hypertension, enalapril has efficacy comparable to that of thiazide diuretics and beta blockers. Side effects observed with enalapril have generally been minor. Captopril-associated side effects such as skin rash, loss of taste, and proteinuria have been observed in a small number of patients receiving enalapril to date; neutropenia less than 300/mm3 has been noted with captopril but not enalapril. The incidence of these side effects has been noted to be greatly decreased in patients on low doses of captopril. Enalapril appears to be similar in efficacy to captopril for treating hypertension and congestive heart failure. Whether enalapril is safer than low-dose captopril in patients at high risk for captopril-associated side effects will require further investigation.     

Comparison of the steady-state pharmacokinetics of fosinopril, lisinopril and enalapril in patients with chronic renal insufficiency.

The phosphinyl ester prodrug fosinopril, a new angiotensin converting enzyme (ACE) inhibitor, is fully hydrolysed after oral administration to the pharmacologically active diacid, fosinoprilat. This metabolite is cleared by both hepatic and renal routes, while most other ACE inhibitors are cleared exclusively by the kidney. In the present study, after administration of multiple fixed oral doses the accumulation of the active moieties of fosinopril, enalapril and lisinopril was compared in patients with renal insufficiency. 29 patients with creatinine clearances (CLCR) less than 30 ml/min received either fosinopril 10mg (n = 9), enalapril 2.5mg (n = 10) or lisinopril 5mg (n = 10) once daily for 10 days in a nonblind (open-label) parallel study. Pharmacokinetic parameters including area under the serum concentration-time curve (AUC), peak serum concentration (Cmax) and time to peak concentration (tmax), as well as renal function, blood pressure, and plasma renin activity (PRA) and aldosterone levels, were determined on the first and last days of the study. The percentage (+/- SEM) increases in AUC from day 1 to day 10 for fosinoprilat, enalaprilat and lisinopril were 26.8 +/- 9.9 (nonsignificant), 76.6 +/- 16.6 (p less than 0.001) and 161.7 +/- 31.8% (p less than 0.001), respectively. These results indicate that there was significantly less accumulation of fosinoprilat, based on accumulation indices, relative to either enalaprilat (p less than 0.05) or lisinopril (p less than 0.001) during the study. The Cmax of fosinopril increased significantly less than that of lisinopril (21.1 vs 123.6%; p less than 0.01). Renal function was not altered in any group, and blood pressure changed modestly.(ABSTRACT TRUNCATED AT 250 WORDS)     

A comparison of lisinopril with enalapril by monitoring plasma angiotensin II levels in humans

The present study was designed to examine and compare the acute effects of lisinopril (20 mg) and enalapril (10 mg) after a single oral administration on the inhibition of the renin-angiotensin system (RAS) in eight normal subjects. Serum concentration of lisinopril and enalaprilat, an active metabolite of enalapril, reached the respective maximal levels at 6 and 4 hr after administration of the drugs. At 24 hr, the serum concentration of lisinopril was higher than that of enalapril; thus the rate of disappearance of lisinopril was retarded, in comparison to that of enalapril. The reduction of serum angiotensin I converting enzyme (ACE) activity was consistent with the pattern of increase of concentration of the drugs in the serum. However, with these two drugs, the concentration of plasma ANG II was decreased in a similar manner, and it returned to the pretreatment level within 24 hr. Thus, there was no significant difference in ANG II levels throughout the 24 hr-study between the lisinopril and enalapril treatment. The results indicate that a single administration of 20 mg lisinopril and 10 mg enalapril show similar potency for lowering the circulating ANG II level, although lisinopril exerts a more sustained inhibition of serum ACE activity. The measurement of ANG II provides useful informations for evaluating the efficacy of ACE inhibitors for the inhibition of circulatory RAS.     

依那普利-氢氯噻嗪治疗原发性高血压的临床疗效

目的:研究依那普利-氢氯噻嗪治疗中国人原发性高血压的临床疗效、安全性和耐受性。方法:采用随机、双盲、平行对照临床试验。126例轻、中度原发性高血压[95mmHg≤平均坐位舒张压(DBP)<110mmHg,平均坐位收缩压(SBP)<180mmHg(1mmHg=0.133kPa)],口服安慰剂2wk后, DBP仍在95-110mmHg的病人,随机分为3组,A组口服依那普利-氢氯噻嗪(10mg:6.25mg),qd;B组口服依那普利-氢氯噻嗪(10mg:12.5mg),qd;C组口服依那普利10mg,qd,4wk后如DBP≥90mmHg,各组剂量均加倍,疗程为8wk。安慰剂期末和治疗2,4,6,8wk测量坐位、立位血压和心率,记录不良反应。结果:8wk末,A组DBP由(99±4)mmHg降至(83±6)mmHg,降低(15±4)mmHg, SBP降低(18±14)mmHg;B组DBP由(100±5)mmHg降至(83±6)mmHg,降低(16±7)mmHg, SBP降低(17±16)mmHg;C组DBP由(97.0±2.0)mmHg降至(89±8)mmHg,降低(8±8)mmHg, SBP降低(3±14)mmHg。各组内DBP与治疗前相比均有非常显著差异(P<0.01),A,B两组组间差异无显著意义(P>0.05),A,B两组降压幅度优于C组,组间比较差异显著(P<0.05)。A,B,C组降压总有效率分别为86％,83％及60％,A,B两组比较无显著差异,分别与C组比较差异显著,优于C组(P<0.05)。3组主要不良反应为咳嗽、干咳,组间比较发生率无显著差异。结论:依那普利-氢氯噻嗪治疗轻、中度原发性高血压疗效优于单药制剂,6.25mg与12.5mg氢氯噻嗪的复方制剂降压疗效相似,复方制剂和单药一样安全,且耐受性好。     

Blood pressure response to conventional and low-dose enalapril in chronic renal failure

AIMS: In chronic renal failure, the clearance of most ACE inhibitors including enalapril is reduced. Hence, with conventional dosage, plasma enalaprilat may be markedly elevated. It is unclear whether this excess of drug exposure affords an improved control of blood pressure. The aim of the present study was to evaluate short-term blood pressure response to two different plasma levels of enalaprilat. METHODS: As part of an open, randomized, controlled trial of the effect of high and low dosage of enalapril on the progression of renal failure, short-term blood pressure response was evaluated. Data were analysed in all patients completing 3 months of follow-up. The patients were allocated to two trough plasma concentrations of enalaprilat, either above 50 ng ml(-1) (high) (n = 17) or below 10 ng ml(-1) (low) (n = 18), and the daily dose of enalapril titrated accordingly. RESULTS: Median (range) glomerular filtration rate (GFR) at baseline was 18 (7.9) in the high enalaprilat concentration group and 17 (7.3) ml min(-1) 1.73 m(2) in the low concentration group (NS). Nine patients in each group were on treatment with enalapril at baseline with a median daily dose of 5 mg in both the high (5-10) and low (2.5-20) concentration group. At 3 months' follow-up, the dose was 10 (2.5-30) and 1.9 (1.25-5) mg (P < 0.0001), respectively. After 3 months median trough concentrations of enalaprilat were 82.5 (22-244) ng ml(-1) and 9.1 (2.5-74.8) ng ml(-1) (P < 0.002). At baseline the median systolic blood pressures in the two groups were 140 (110-200) and 133 (110-165), in the high and low enalaprilat concentration groups, respectively, and after 3 months they were 135 (105-170) and 130 (105-170) mmHg (NS). Median diastolic blood pressure was 80 mmHg in each group both at baseline (65-100) and at follow-up (60-95) (NS). There was no difference between the groups in concomitant antihypertensive treatment (number of patients treated, mean daily dose) during the observation period. Proteinuria remained stable during the study period in both groups; patients in the high concentration group had higher plasma potassium concentrations at day 90 and patients in the low group experienced a slight increase in GFR. CONCLUSIONS: In moderate to severe chronic renal insufficiency the same degree of blood pressure control was achieved on low as well as moderate daily doses of enalapril. This was irrespective of concomitant antihypertensive treatment.     

The effects of age on the pharmacokinetics and pharmacodynamics of single oral doses of benazepril and enalapril.

1. Eighteen healthy, normotensive subjects (nine young and nine elderly) participated in a double-blind, 3-way, crossover study to compare aspects of the pharmacokinetics and pharmacodynamics of single oral doses of 10 mg benazepril, 10 mg enalapril and placebo. 2. The hypotensive effect was similar after both drugs but the absolute reductions were greater in the elderly who had higher initial levels of blood pressure. 3. The AUCs for both benazeprilat and enalaprilat were higher in the elderly but by a significantly greater amount for enalaprilat (+ 113% vs 40%; P < 0.01). 4. The AUCs for both drugs tended to be highest in subjects with the lowest creatinine clearance. 5. The changes in kinetics and dynamics observed in the elderly after benazepril are qualitatively similar to those with other ACE inhibitors. The clinical significance of the quantitative differences requires further investigation.     

Greater blood pressure-lowering effect of the renin inhibitor EMD 58265 than an angiotensin-converting enzyme inhibitor in two-kidney one-clip Goldblatt rabbit

1. Renin inhibitors may be more advantageous than either angiotensin-converting enzyme (ACE) inhibitors or angiotensin (Ang) antagonists in blocking the renin-angiotensin system (RAS) because they do not allow accumulation of either AngI or AngII in plasma. 2. Effects of i.v. administration of two human renin inhibitors (EMD 58265 and U 71038) were compared with the ACE inhibitor enalaprilat on mean blood pressure (BP), renal blood flow (RBF) and plasma AngI and AngII in the anaesthetized two-kidney one-clip Goldblatt rabbit. 3. At doses of 2-2.5 mg/kg, i.v., EMD 58265 and 5-10 mg/kg, i.v., U 71038, both drugs decreased BP approximately 10 mmHg more than enalaprilat (2-4 mg/kg, i.v.) when given either before or after the ACE inhibitor. None of the three agents had any significant effect on RBF in the face of the lowered BP; however, renal vascular resistance was decreased. A higher dose of enalaprilat (10 mg/kg, i.v.) had no further effect on BP than the lower doses but did cause a marked increase in RBF. 4. Both renin inhibitors markedly decreased plasma AngI, but the high basal level of AngII was less consistently and only modestly affected. Enalaprilat, in either the low dose range or at the high dose, was also not effective in significantly decreasing AngII. 5. The results indicate that renin inhibition in the rabbit with a high circulating AngII level is more effective in lowering BP than ACE inhibition. A high dose of the ACE inhibitor may be required to block the intrarenal RAS, which may account for the increase in RBF.     

An evaluation of the pharmacodynamics and pharmacokinetics of nicardipine combined with enalapril in essential hypertension

Recent observations suggest that calcium antagonists may enhance the antihypertensive effects of angiotensin-converting enzyme (ACE) inhibitors. Twelve essential hypertensives who had blood pressures greater than 160/90 after a minimum of 6 weeks of monotherapy with the ACE inhibitor enalapril 20 mg daily received additional treatment with nicardipine 30 mg t.i.d. and placebo, each for 2 weeks, in a double-blind crossover study. The combination of nicardipine with enalapril was well tolerated. The addition of the first dose of nicardipine was associated with significant reductions (p less than 0.05) in blood pressure during the first 4 h: from a baseline of 165/99 to 128/80 (supine) at 2 h after nicardipine as compared with 167/101-146/90 following placebo. Two weeks of combined treatment with nicardipine and enalapril significantly reduced the predosing blood pressure, 12 h after the last dose of nicardipine (158/96 as compared with 172/106 with placebo), and there were further significant reductions in blood pressure during the subsequent dosage interval. The profile of plasma ACE inhibition and the pharmacokinetics of enalaprilat were unaffected by the addition of nicardipine. These results suggest that nicardipine and enalapril are an effective and well-tolerated antihypertensive combination.     

The pharmacokinetics of enalapril in patients with compensated liver cirrhosis.

The possibility of an impaired hepatic de-esterification of enalapril to enalaprilat due to hepatic dysfunction was assessed in seven patients with compensated liver cirrhosis and 10 normal control subjects. The peak serum concentration and time to the peak serum concentration of enalaprilat, as well as the suppression of serum angiotensin converting enzyme activity, following a single oral dose of enalapril maleate (10 mg) were not different in the two groups. The elimination half-life of enalaprilat was related to renal function. The results suggest that hepatic biotransformation of the drug may not be disturbed in a clinically significant manner in patients with moderate hepatic dysfunction due to compensated liver cirrhosis.     

Pharmacokinetics and pharmacodynamics of a nitric oxide-releasing derivative of enalapril in male beagles

1. Pharmacological compounds that release nitric oxide (NO) have been useful tools in the evaluation of the broad role of NO in physiopathology and therapeutics. The present study compared the pharmacokinetics and pharmacodynamics of enalapril and an NO-releasing enalapril molecule (NCX899) in conscious male beagles. The effects of both enalapril and NCX899 in the arterial hypertension and bradycardia induced by acute NO inhibition in anaesthetized dogs were also investigated. 2. Dogs received either NCX899 (4 micromol/kg, i.v.) or enalapril (4 micromol/kg, i.v.), after which plasma concentrations of the analytes and metabolites were quantified by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). 3. In the NCX899 group, the area under the time-course curve (AUC(0-24h)) was 29.18 +/- 4.72, 229.37 +/- 51.32 and 5159.23 +/- 514.88 microg.h/L for the analytes nitro-enalapril, enalapril and enalaprilat, respectively. In the enalapril group, the AUC(0-24h) was 704.53 +/- 158.86 and 4149.27 +/- 847.30 microg.h/L for the analytes enalapril and enalaprilat, respectively. Statistical analysis of data from both groups showed a significant difference for the analyte enalapril, but not for enalaprilat. Moreover, NCX899 and enalapril were equally effective in inhibiting the activity of serum angiotensin-converting enzyme. 4. In anaesthetized dogs, i.v. administration of the NO synthase (NOS) inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME; 0.1-10 mg/kg) significantly elevated arterial blood pressure, with concomitant bradycardia. The compound NCX899 significantly attenuated both arterial hypertension and bradycardia, whereas enalapril had no significant effect. 5. In conclusion, the present results showed that the NO-releasing derivative of enalapril NCX899 presents a pharmacokinetic/pharmacodynamic relationship similar to its parent compound enalapril. Moreover, NCX899 (but not enalapril) was effective in protecting against the cardiovascular changes induced by acute NOS inhibition.     

Pharmacokinetics,safety, and antihypertensive efficacy of losartan in combination with hydrochlorothiazide in hypertensive patients with renal impairment

The pharmacokinetics and pharmacodynamics of 7 days of treatment with losartan 50 mg/hydrochlorothiazide 12.5 mg were evaluated in 14 patients with normal renal function and in 12 patients with mild to moderate renal impairment. The efficacy of losartan 50 mg/hydrochlorothiazide 12.5 mg titrated to losartan 100 mg/hydrochlorothiazide 25 mg was examined in 32 hypertensive patients with mild to moderate renal impairment who were treated for 12 weeks. Safety was assessed in both studies by the incidence of adverse experiences. After 7 days of treatment, the AUC for losartan, E-3174, and hydrochlorothiazide was slightly higher in patients with mild to moderate renal impairment, but the reduction in blood pressure (BP) after 7 days was not different between the two groups. The final (week 12) mean reductions in trough sitting diastolic and systolic BP were 15.0 +/- 7.1 mmHg (p < 0.01) and 20.8 +/- 16.7 mmHg (p < 0.01), respectively. There were no observed increases in drug-related adverse experiences in either study. Overall, the combination of losartan/hydrochlorothiazide was effective in lowering blood pressure and was well tolerated in patients with mild to moderate renal impairment.