Class Of Angiotensin-converting Enzyme Inhibitors Research Articles

Role of lisinopril in the therapeutic management of cardiovascular disease by targeting microtubule affinity regulating kinase 4: molecular docking and molecular dynamics simulation approaches

Cardiovascular diseases (CVDs) are a major cause of premature adult death. Various factors contribute to the development of CVDs, such as atherosclerosis leading to myocardial infarction (MI), and compromised cardiac function after MI leads to chronic heart failure with systemic health complications and a high mortality rate. Microtubule detyrosination has rapidly evolved as an essential mechanism to regulate cardiomyocyte contractility. Microtubule affinity regulating kinase 4 (MARK4) regulates cardiomyocyte contractility in a way that it promotes phosphorylation of microtubule-associated protein 4, thereby facilitating the access of vasohibin 2—a tubulin carboxypeptidase—to microtubules for the detyrosination of α-tubulin. Lisinopril, a drug belonging to the class of angiotensin-converting enzyme inhibitors, is used to treat high blood pressure. This is also used to treat heart failure, which plays a vital role in improving the survival rate post-heart attack. In this study, we will evaluate the MARK4 inhibitory potential of lisinopril employing molecular docking and molecular dynamics (MD) simulation approaches. Molecular docking analysis suggested that lisinopril binds to MARK4 with a significant binding affinity forming interactions with functionally essential residues of MARK4. Additionally, MD simulation deciphered the structural dynamics and stability of the MARK4–lisinopril complex. The findings of MD studies established that minimal structural deviations are observed during simulation, affirming the stability of the MARK4–lisinopril complex. Altogether, this study demonstrates lisinopril’s crucial role in the therapeutic management of CVD by targeting MARK4. Communicated by Ramaswamy H. Sarma

Patient views of therapeutic interchange of ACE inhibitors in Australian primary care: a qualitative study

ObjectivesIn Australia, therapeutic interchange of angiotensin-converting enzyme (ACE) inhibitors could generate savings for patients and the Pharmaceutical Benefits Scheme (PBS). The PBS subsidises nine drugs in the ACE inhibitor class....

Evaluation of angiotensin converting enzyme inhibitors (ACEI) induced side effects in allergology department

Background and aim. ACEIs are extensively used in cardiac diseases and among their main side effects there are dry cough and angioedema. The aim of this study is to evaluate the patients who are presenting to an allergologist for a suspicion of side effects induced by ACEI. Material and methods. Forty-two patients with arterial hypertension treated with ACEI, who have presented dry cough and/or angioedema as side effects, were included. The patients were evaluated between 2014 and 2016 in one allergology department from Cluj-Napoca. The data were collected from the files and were statistically analyzed using SPSS v.21. The allergological evaluation included anamnesis data that were recorded in patients files and the results of skin prick test performed at the initial presentation. Results. Females were more likely than men to have side effects (64.3% versus 35.7%). Half of the patients were treated with perindopril. Most of the patients (59.5%) were referred to the allergology department for dry cough. Angioedema was more commonly observed in men, while cough was a frequent side effect in women, with no statistical significance (p = 0.150). There is no correlation between the used ACEI and the type of side effect (p = 0.45) or the number of angioedema episodes (p = 0.51). The persistence of the symptoms in spite of treatment cessation was observed in case of perindopril and enalapril (p = 0.05) and in case of atopy presence (p = 0.03). Conclusions. Cough and angioedema are common side effects of the whole class of ACEI. The type of adverse events might be correlated with the patient’s gender. The presence of atopy may increase the risk of symptoms persistence.

Discovery of a potent angiotensin converting enzyme inhibitor via virtual screening

Prompted by the prominent role of angiotensin converting enzyme (ACE) in hypertension, heart failures, myocardial infarction and diabetic nephropathy, we have attempted to discover novel ACE inhibitors through ligand-based virtual screening. Molecular docking method and rigorously validated model was utilized to search a natural compounds database. Finally, 36 compounds were randomly selected and subjected to in vitro ACE kinase inhibitory assay using fluorescence assays method. The results showed that three compounds (Licochalcone A, Echinatin and EGCG) have strong potential to be developed as a new class of ACE inhibitors. Further chemical modification via fragment modifications guided by structure and ligand-based computational methodologies can lead to discover better agents as potential clinical candidates.

FDA Approves First-in-Class Combo Drug for Heart Failure

FDA Approves First-in-Class Combo Drug for Heart Failure

The most critical question when reading a meta-analysis report: Is it comparing apples with apples or apples with oranges?

Objective:While the number of meta-analyses published has increased recently, most of them have problems in the design, analysis, and/or presentation. An example of meta-analyses with a study selection bias is a meta-analysis of over 160,000 patients in 20 clinical trials, published in Eur Heart J in 2012 by van Vark, which concluded that the significant effect of renin-angiotensin-aldosterone system (RAAS) inhibition on all-cause mortality was limited to the class of angiotensin-converting enzyme inhibitors (ACEIs), whereas no mortality reduction could be demonstrated with angiotensin receptor blockers (ARBs). Here, we aimed to discuss how to select studies for a meta-analysis and to present our results of a re-analysis of the van Vark data.Methods:The data were re-analyzed in three steps: firstly, only ACEI/ARB-based studies (4 ACEI and 12 ARB studies) were included; secondly, placebo-controlled studies were excluded, and 10 studies left were analyzed; and thirdly, 2 studies that were retracted after the manuscript of van Vark had been published were excluded. The final analysis included 8 studies with ~65,000 patients (3 ACEI and 5 ARB studies).Results:The hazard ratios for all-cause mortality and cardiovascular mortality were 0.992 (95% CI 0.899-1.095; p=0.875) and 1.017 (0.932-1.110; p=0.703) for the ACEI versus control group and 1.007 (0.958-1.059; p=0.778) and 0.967 (0.911-1.025; p=0.258) for the ARB versus control group in the first step. The results were similar in the second and third steps.Conclusion:The studies to be included in meta-analyses, particularly comparing ACEIs and ARBs, should be chosen carefully.

Costs of current antihypertensive therapy in Switzerland: an economic evaluation of 3,489 patients in primary care

Due to greater life expectancy, costs of medication have increased within the last decade. This investigation assesses health care expenditures needed to manage the current state of blood pressure (BP) control in Switzerland. a) average day therapy costs (DTC) of substances, b) actual DTC of currently prescribed antihypertensive therapy, c) monetary differences of treatment regimens within different BP-groups and different high risk patients, d) estimated compliance-related financial loss/annum and adjusted costs/annum. Single-pill-combinations appear to be useful to increase patient's compliance, to reduce side effects and to bring more patients to their blood pressure goal. Costs were identified based on data from the Swiss department of health. We calculated DTC for each patient using prices of the largest available tablet box. The average antihypertensive therapy in Switzerland currently costs CHF 1.198 ± 0.732 per day. On average beta blockers were the cheapest substances, followed by angiotensin converting enzyme inhibitors (ARBs), calcium channel blockers and diuretics. The widest price ranges were observed within the class of ARBs. Most expensive were patients with impaired renal function. Throughout all stages, single-pill-combinations appeared to be significantly cheaper than dual-free-combinations. Stage-II-hypertension yielded the highest costs for dual free combination drug use. The actual costs for all patients observed in this analysis added up to CHF 1,525,962. Based on a compliance model, only treatment amounting to CHF 921,353 is expected to be actually taken. A disproportionately high healthcare cost is expected due to compliance reasons. The prescription of mono-therapies appears to be a major cost factor, thus, the use of single-pill-combination therapy can be considered as a suitable approach to saving costs throughout all BP- stages.

Not All Angiotensin-Converting Enzyme Inhibitors Are Equal: Focus on Ramipril and Perindopril

Angiotensin-Converting enzyme (ACE) inhibitors are a heterogeneous class, varying in pharmacologic properties, which have different therapeutic impacts on patient profiles, including lipophilicity, tissue-ACE binding, duration of action, half-life, and increased bradykinin availability. Among the ACE inhibitor class, the agent Perindopril, in particular, has pleiotropic effects that are not equally shared by other ACE inhibitors, including bradykinin site selectivity and subsequent enhancement of nitric oxide and inhibition of endothelial cell apoptosis. Moreover, there is a large amount of evidence to suggest that Perindopril therapy may reduce cardiovascular event rates in patients, yet Perindopril is rarely prescribed in the United States. Ramipril is another ACE inhibitor with both a favorable clinical profile and impressive outcomes data. Our review compares the pharmacologic and trial data among Perindopril, ramipril, and other ACE inhibitors. In patients with or at high risk for coronary heart disease who do not have heart failure, or in patients with heart failure with preserved ejection fraction, Perindopril should be among the preferred treatment agents in the ACE inhibitor class. Ramipril has an impressive track record of improving cardiovascular outcomes, too, and should be considered a preferred agent among the ACE inhibitor class.

Angiotensin-converting enzyme inhibitors reduce mortality in hypertension: a meta-analysis of randomized clinical trials of renin-angiotensin-aldosterone system inhibitors involving 158 998 patients

AimsRenin–angiotensin–aldosterone system (RAAS) inhibitors are well established for the reduction in cardiovascular morbidity, but their impact on all-cause mortality in hypertensive patients is uncertain. Our objective was to analyse the effects of RAAS inhibitors as a class of drugs, as well as of angiotensin-converting enzyme (ACE) inhibitors and AT1 receptor blockers (ARBs) separately, on all-cause mortality.Methods and resultsWe performed a pooled analysis of 20 cardiovascular morbidity–mortality trials. In each trial at least two-thirds of the patients had to be diagnosed with hypertension, according to the trial-specific definition, and randomized to treatment with an RAAS inhibitor or control treatment. The cohort included 158 998 patients (71 401 RAAS inhibitor; 87 597 control). The incidence of all-cause death was 20.9 and 23.3 per 1000 patient-years in patients randomized to RAAS inhibition and controls, respectively. Overall, RAAS inhibition was associated with a 5% reduction in all-cause mortality (HR: 0.95, 95% CI: 0.91–1.00, P= 0.032), and a 7% reduction in cardiovascular mortality (HR: 0.93, 95% CI: 0.88–0.99, P= 0.018). The observed treatment effect resulted entirely from the class of ACE inhibitors, which were associated with a significant 10% reduction in all-cause mortality (HR: 0.90, 95% CI: 0.84–0.97, P= 0.004), whereas no mortality reduction could be demonstrated with ARB treatment (HR: 0.99, 95% CI: 0.94–1.04, P= 0.683). This difference in treatment effect between ACE inhibitors and ARBs on all-cause mortality was statistically significant (P-value for heterogeneity 0.036).ConclusionIn patients with hypertension, treatment with an ACE inhibitor results in a significant further reduction in all-cause mortality. Because of the high prevalence of hypertension, the widespread use of ACE inhibitors may result in an important gain in lives saved.

Antioxidant activity of peptide-based angiotensin converting enzyme inhibitors

Angiotensin converting enzyme (ACE) inhibitors are important for the treatment of hypertension as they can decrease the formation of vasopressor hormone angiotensin II (Ang II) and elevate the levels of vasodilating hormone bradykinin. It is observed that bradykinin contains a Ser-Pro-Phe motif near the site of hydrolysis. The selenium analogues of captopril represent a novel class of ACE inhibitors as they also exhibit significant antioxidant activity. In this study, several di- and tripeptides containing selenocysteine and cysteine residues at the N-terminal were synthesized. Hydrolysis of angiotensin I (Ang I) to Ang II by ACE was studied in the presence of these peptides. It is observed that the introduction of L-Phe to Sec-Pro and Cys-Pro peptides significantly increases the ACE inhibitory activity. On the other hand, the introduction of L-Val or L-Ala decreases the inhibitory potency of the parent compounds. The presence of an L-Pro moiety in captopril analogues appears to be important for ACE inhibition as the replacement of L-Pro by L-piperidine 2-carboxylic acid decreases the ACE inhibition. The synthetic peptides were also tested for their ability to scavenge peroxynitrite (PN) and to exhibit glutathione peroxidase (GPx)-like activity. All the selenium-containing peptides exhibited good PN-scavenging and GPx activities.

Renal handling of angiotensin receptor blockers: clinical relevance.

Angiotensin receptor blockers (ARBs), like angiotensin-converting enzyme (ACE) inhibitors, are commonly used in the setting of chronic kidney disease. The use of drugs in this class, or for that matter any drug in the renally compromised patient, should raise consideration of the impact of renal disease on the systemic elimination of the compound. Unlike most of the drugs in the ACE inhibitor class, the compounds making up the ARB class undergo significant hepatic elimination; thus, in the renal failure patient, they are not prone to relevant degrees of systemic accumulation with repetitive dosing. ARBs do not require dose adjustment in renal failure on the basis of their pharmacokinetic pattern; rather, dose reduction should be an empiric process dictated by having reached or exceeded the goal established for blood pressure reduction.

Comparison of the renal effects of different angiotensin-converting enzyme inhibitors in patients with chronic renal diseases

Background. Angiotensin-converting enzyme inhibitors (ACE-Is) are important agents for preserving renal function in patients with renal diseases. However, the choice of which ACE-I to employ for the treatment of renal disease has not yet been clarified. This study compared the renal effects of enalapril with those of five other ACE-Is in patients with chronic renal diseases. Methods. One hundred and twenty-eight patients with various renal diseases were randomly assigned to six groups according to the ACE-I used: group 1, alacepril (75 mg/day; n = 20); group 2, captopril (37.5 mg/day; n = 19); group 3, cilazapril (1.0 mg/day; n = 23); group 4, delapril (30 mg/day; n = 22); group 5, enalapril (5.0 mg/day; n = 20); and group 6, temocapril (2.0 mg/day; n = 24). Doses of the ACE-I adjusted-converting to the renal function showed similar effects in decreasing blood pressure. Each ACE-I was administered to the patients for 4 months, with monthly examinations. Twenty-four patients dropped out, for various reasons; therefore, results for 104 patients were finally analyzed (group 1, n = 16; group 2, n = 11; group 3, n = 22; group 4, n = 21; group 5, n = 12; group 6, n = 22). Results. There were no differences in absolute or percent changes in mean arterial pressure (MAP), plasma aldosterone (ALDO), the urinary excretion of protein (U-P) and albumin (U-ALB), 24-h creatinine clearance (24-h Ccr), plasma renin activity (PRA), and serum potassium (K) between enalapril and the other ACE-Is, although significant decreases from baseline values in MAP, ALDO, U-P, U-ALB, and 24-h Ccr, and increases in PRA and serum K from baseline values were observed after the administration of enalapril and the other ACE-Is. Conclusions. These results indicated that the renal effects of enalapril were similar to those of the other ACE-Is tested, and suggested, therefore, that any one of the class of ACE-Is could be chosen with the choice being dependent on that considered to lead to best compliance for the patient. The beneficial effects of the class of ACE-Is in patients with renal disease would be expected to be similar.

Human serum albumin induced hypotension in the postoperative phase of cardiac surgery.

Hypotension associated with the rapid infusion of human serum albumin products was first recognised in Australasia in the early 1970s. An association with the angiotensin converting enzyme inhibitor class of drugs (ACE-I) followed, leading to a proposed mechanism involving bradykinin generation through pre-kallikrein activator (PKA) presence in the infused fluid. The newer generation albumin products (Albumex) contain very low concentrations of PKA and are generally thought safe to use in most patient populations. Anecdotal reports of paradoxical hypotension with rapid infusion of 4% albumin in our department led to an audit of practice over three months. Four out of 36 patients (11%) who received 4% albumin intravenously experienced paradoxical hypotension. Three of these patients were taking ACE-I preoperatively (P=0.04). There was no observed hypotension associated with intravenous infusion of crystalloid fluid. We believe 4% albumin should be used with caution, particularly in those patients receiving ACE-I preoperatively.

Overview of the angiotensin-converting-enzyme inhibitors.

The pharmacology of angiotensin-converting-enzyme (ACE) inhibitors and their role in the renin-angiotensin system (RAS) are described, and pharmacokinetic properties and common adverse events are presented. ACE inhibitors play a vital role in the RAS by regulating the potent vasoconstrictor angiotensin II. All ACE inhibitors share the same basic structure; however, they can be separated on the basis of their functional (binding) group: carboxyl, sulfhydryl, or phosphinyl. These functional groups are, in part, responsible for differences in the pharmacokinetic and safety profiles of these agents. Captopril and lisinopril are the only ACE inhibitors that are not prodrugs requiring activation through hepatic biotransformation. Differences among the ACE inhibitors in lipophilicity are described; fosinopril has the greatest lipophilicity and lisinopril the least. ACE is found in numerous tissues, and there is increasing evidence of differences among ACE inhibitors in their ability to inhibit tissue ACE. Most ACE inhibitors are eliminated mainly by the kidneys and to a lesser extent through the liver. Lisinopril is the only ACE inhibitor that does not require hepatic metabolism. In the selection of an ACE inhibitor for once-daily use to treat hypertension, differences in trough-peak ratios are clinically relevant. Fosinopril, ramipril, and trandolapril have minimum trough-peak ratios of 50% or greater. ACE inhibitors are generally well tolerated, with hypotension, cough, and hyperkalemia being the most frequently reported adverse effects for the entire class. Drug interactions across the ACE inhibitor class as well as agent-specific interactions are described. Factors to be considered in the selection of an ACE inhibitor include differences in potency, affinity for ACE, pharmacokinetics, and toxicity that are related to structural properties of the drug; whether the trough-peak ratio enables use of a once-daily dose; and potential adverse effects related to a drug's functional (binding) group.

A New Treatment forInterdialytic Hyperkalemia – The Use of Fosinopril Sodium

Fosinopril sodium is the first of the phosphinic acid class of angiotensin-converting enzyme inhibitors (ACEI). It is used as an antihypertensive agent, but differs from other ACEI in its dual routes of excretion (liver and kidney), and less incidence of hyperkalemia and cough. We conducted a study in known chronic hemodialysis patients who developed interdialytic hyperkalemia in spite of other treatments to control hyperkalemia. We used fosinopril in this group of patients to assess the effect of fosinopril on serum potassium (K) levels. Twenty-four patients were given fosinopril 10 mg at 18:00 h daily for 8 weeks. K levels were measured before and after each dialysis treatment. Interdialytic weight gains were recorded. The average pretrial potassium level was 6.57 mmol/l (± 0.47), and the posttrial level was 5.34 (± 0.76); p ≤ 0.0001. No statistically significant interdialytic weight gain or reduction occurred. No first dose hypertensive effect or cough were reported. We have found the use of fosinopril to be successful in lowering predialysis serum K levels in hyperkalemic dialysis patients.

ACE inhibitor potentiation of bradykinin-induced venoconstriction.

1. Angiotensin-converting enzyme (ACE) inhibitors exert their cardiovascular effects not only by preventing the formation of angiotensin II (AII), but also by promoting the accumulation of bradykinin in or at the vessel wall. In addition, certain ACE inhibitors have been shown to augment the vasodilator response to bradykinin, presumably by an interaction at the level of the B2 receptor. We have investigated whether this is a specific effect of the ACE inhibitor class of compounds in isolated endothelium-denuded segments of the rabbit jugular vein where bradykinin elicits a constrictor response which is exclusively mediated by activation of the B2 receptor. 2. Moexiprilat and ramiprilat (< or = 3 nM) enhanced the constrictor response to bradykinin three to four fold. Captopril and enalaprilat were less active by approximately one and quinaprilat by two orders of magnitude. Moexiprilat and ramiprilat, on the other hand, had no effect on the constrictor response to AII or the dilator response to acetylcholine. 3. The bradykinin-potentiating effect of the ACE inhibitors was not mimicked by inhibitors of amino-, carboxy-, metallo- or serine peptidases or the synthetic ACE substrate, hippuryl-L-histidyl-L-leucine, at a concentration which almost abolished the residual ACE activity in the vessel wall. In contrast, angiotensin-(1-7) (10 microM), an angiotensin I metabolite, significantly enhanced the constrictor response to bradykinin. 4. Ramiprilat did not alter the binding of [3H]-bradykinin to a membrane fraction prepared from endothelium-denuded rabbit jugular veins or to cultured fibroblasts, and there was no ACE inhibitor-sensitive, bradykinin-induced cleavage of the B2 receptor in cultured endothelial cells. 5. These findings demonstrate that ACE inhibitors selectively potentiate the B2 receptor-mediated vascular effects of bradykinin. Their relative efficacy appears to be independent of their ACE-inhibiting properties and might be related to differences in molecule structure. Moreover, the potentiation of the biological activity of bradykinin by this class of compounds does not seem to be mediated by a shift in affinity of the B2 receptor or a prevention of its desensitization, but may involve an increase in the intrinsic activity of unoccupied B2 receptor molecules.

Abnormal taurocholate ileal transepithelial transport in atherosclerotic mini-pigs and effects of ace inhibitors

In atherosclerotic mini-pigs, we attempted to determine (i) whether high-fat atherogenic diet disturbs the taurocholate transepithelial transport and incorporation in the ileal epithelium mounted in Ussing chambers, and (ii) whether these processes are sensitive to angiotensin converting enzyme (ACE) inhibitors which slow the development of vascular atherosclerosis. In atherosclerotic mini-pigs, the mucosal to serosal transepithelial fluxes were markedly lower (72% inhibition) and free diffusion was more altered than active processes. Taurocholate incorporation into enterocyte (75% inhibition) paralleled the flux reduction. The transport disturbance observed here might be explained by changes in bile salt permeability in relation to alterations of the membrane properties. Taurocholate absorption was lowered by atherogenic diet, whereas bile salts were not trapped in the enterocyte, therefore atherosclerosis-induced alterations preferentially affected the passage through the brush-border. In the ACE inhibitor treated atherosclerotic mini-pigs, perindopril and enalapril similarly inhibited serum ACE activities. Perindopril further corrected taurocholate fluxes by 50% and fully restored taurocholate incorporation. Since enalapril did not restore the atherosclerosis-induced alterations, the involvement of intestinal ACE in bile acid recycling and of an ACE inhibitor class effect on these mechanisms both remain to be ascertained.

Pharmacokinetics and biochemical efficacy of idrapril calcium, a novel ACE inhibitor, after multiple oral administration in humans.

The pharmacokinetic profile and biochemical efficacy of idrapril calcium, a novel angiotensin converting enzyme (ACE) inhibitor, were evaluated in healthy volunteers after multiple dosing for 5 days at the doses of 100, 200 and 400 mg twice daily. The study was conducted as a double-blind, cross-over comparison of idrapril calcium against placebo. Plasma concentrations of idrapril were determined by an indirect enzymatic method. Urinary concentrations were measured by reverse phase high performance liquid chromatography (h.p.l.c.). Plasma samples were also analysed for ACE activity. The pharmacokinetics of idrapril calcium did not change significantly between day 1 and day 5. The values of Cmax and AUC were dose-related over the range of doses tested; tmax was 3-4 h and apparent elimination half-life was 1.4-1.6 h. Plasma ACE activity was maximally inhibited (94-96%) at all dose levels and remained more than 80% depressed from 2 to at least 6 h after idrapril calcium. Although the maximum effect was not dose-related, the duration of inhibition showed some dose-dependency, ACE activity returning to 56, 45 and 29% of the basal value 12 h after the 100, 200 and 400 mg doses, respectively. There were no clinically significant adverse events experienced by the volunteers. No dose-related effects on blood pressure or heart rate were observed. There were no changes in clinical pathology tests, urine analyses or electrocardiograms after dosing with idrapril calcium. Idrapril calcium, the prototype of a new class of ACE inhibitors, appears to be well-tolerated.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical Pharmacokinetics of Angiotensin Converting Enzyme (ACE) Inhibitors in Renal Failure

Arterial hypertension occurs frequently in patients with chronic renal failure. Antihypertensive treatment of arterial hypertension with angiotensin converting enzyme (ACE) inhibitors has been shown to be effective with a low incidence of adverse effects compared with other drug classes. Furthermore, treatment with ACE inhibitors may slow the progression of renal function impairment in certain groups of patients, such as those with diabetes. Most ACE inhibitors are prodrugs which are converted by hepatic esterolysis to an active diacid metabolite. Only captopril and lisinopril have sufficient oral bioavailability and are given as active drugs. ACE inhibitors can be subdivided into 3 classes with regard to the active group: the majority of ACE inhibitors are carboxyl-containing drugs, a new class of ACE inhibitors possess a phosphoryl-group and captopril and related compounds are sulfhydryl-containing drugs. The predominant elimination pathway of ACE inhibitors is excretion via the kidneys. Therefore, renal insufficiency is associated with reduced elimination of most ACE inhibitors and, thus, altered pharmacokinetic properties. This is most evident in chronic renal failure when glomerular filtration rates (GFR) are < 30 to 40 ml/min (1.8 to 2.4 L/h). As renal clearance decreases, the peak plasma concentration and area under the plasma concentration-time curve of the active drugs or diacids are increased and time to peak concentrations and half-life are prolonged. However, there are large between-drug differences in the changes in pharmacokinetic parameters, resulting in different degrees of drug accumulation after consecutive administration. This leads, for example, to high accumulation rates for drugs such as lisinopril, or cilazaprilat. In contrast, fosinopril, which is also excreted to a large extent by the hepatobiliary pathway, does not seem to accumulate in renal failure. In general, pharmacokinetics and conversion of prodrugs seem to be slightly affected in chronic renal failure; however, these changes do not appear to be clinically relevant. Efficiency of clearance for prodrugs or active drugs and their respective metabolites by haemodialysis or peritoneal dialysis varies considerably. For some ACE inhibitors, such as captopril or enalapril, the high elimination fraction by haemodialysis necessitates a supplemental dose after dialysis. Other ACE inhibitors, such as quinapril or cilazapril, are only poorly eliminated by haemodialysis or peritoneal dialysis. Dosage recommendations for treatment with ACE inhibitors in chronic renal failure depend on the specific pharmacokinetic properties of the various agents. For most ACE inhibitors, dosage adjustment is recommended in moderate and severe impairment of renal function, with resultant dosages being 25 to 50% of those recommended for patients with normal renal function.

Radioimmunoassay for ceronapril, a new angiotensin-converting enzyme inhibitor, and its application to a pharmacokinetic study in healthy male volunteers.

Ceronapril is a member of a new chemical class of angiotensin-converting enzyme inhibitors being developed by The Bristol-Myers Squibb Pharmaceutical Research Institute. A radioimmunoassay (RIA) has been developed for the measurement of ceronapril in biological fluids. The RIA has a range of 0 to 500 ng/ml and has the sensitivity to detect 1.0 ng/ml of ceronapril. Satisfactory zero binding and sensitivity were obtained after a 2-h incubation at room temperature or overnight at 4 degrees C. Separation of the antibody-bound and free radiolabel was achieved by employing polyethylene glycol-goat anti-rabbit gamma-globulin separant. A quantitative recovery of the exogenous analyte was obtained at all concentrations of ceronapril tested. Intraassay coefficients of variance (CV's) were 3.9% and 4.6% for the low and medium controls, respectively. A highly significant statistical correlation between RIA and [14C]TLRC was observed for both plasma and urine samples. Clinical samples from the ascending dosage studies have been analyzed by the ceronapril RIA. The maximum concentration and the area under the plasma concentration-time curve did not increase in a dose-proportional manner for doses above 100 mg.