spirapril and spiraprilat

Spirapril is a new angiotensin-converting enzyme (ACE) inhibitor. It is a prodrug with a resorption of about 50%. The active metabolite spiraprilat reaches maximal plasma concentration within 2-3 h after oral administration. Spirapril can be administered once daily because of its long duration of action caused by an elimination half-life of about 40 h. It undergoes renal and hepatic elimination. In contrast to other ACE inhibitors it has a narrow dose range; therefore, the recommended dose is 6 mg for most patients without the need for dose titration. Spirapril has no relevant drug interactions. In several studies, spirapril was given to patients with mild-to-moderate essential hypertension at doses of 1-24 mg/day. There was an identical blood pressure lowering effect at doses of 6-24 mg/day; doses of 1-3 mg/day were less effective. Twenty-four-hour blood pressure monitoring showed a trough:peak ratio up to 0.84. In studies comparing the effect of spirapril with enalapril, lisinopril, trandolapril or captopril, spirapril was at least as effective as the other substances. Besides treating uncomplicated mild-to-moderate essential hypertension, spirapril can be used in patients with diseases accompanying hypertension such as heart and renal diseases, diabetes mellitus, and lipid disturbances. Possible advantages of spirapril compared to other ACE inhibitors are the dual mechanism of elimination, the lack of need for dose titration and a low incidence of cough.

Topics: Angiotensin-Converting Enzyme Inhibitors; Clinical Trials as Topic; Drug Interactions; Enalapril; Humans; Hypertension; Prodrugs

Spirapril is a recent ACE inhibitor with a both renal and hepatic elimination pathway. In order to determine its tolerability, primarily the impact on renal function, Spirapril was tested in a single-blind trial with a 2-week placebo run-in phase and a 4-week active treatment period. Forty-nine patients (34 males and 15 females) with varying degrees of renal impairment were included. Their pretreatment diastolic blood pressure (DBP) ranged from 95 to 115 mm Hg. Spirapril was administered in oral doses of 6 mg once daily.. Forty-four patients completed the study. Four patients dropped out due to side effects, 1 patient was withdrawn from the study due to lack of antihypertensive efficacy. 48% of the completers with renal failure achieved a normalized diastolic blood pressure (DBP < or = 90 mm Hg) or a reduction in DBP of > or = 10 mm Hg; the corresponding figure for patients with normal renal function was 31%. Renal function was assessed in the beginning and at the end of the active Spirapril treatment period using Tc-99m-DTPA-clearance (representing glomerular filtration rate), J-131-hippuran-clearance (representing renal plasma flow) and creatinine clearance. Particularly in patients with renal impairment, Spirapril did not deteriorate renal function as given by these parameters. Regression analysis revealed a linear correlation between total plasma clearance of the active metabolite Spiraprilate and creatinine clearance. There was no evidence for drug accumulation.. In patients with renal impairment the pharmacokinetic results indicate a non-renal elimination of the drug. Spirapril 6 mg once daily is concluded to be a well tolerated antihypertensive therapy for patients with mild to moderate hypertension and varying degrees of chronic renal failure.

Topics: Administration, Oral; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Creatinine; Enalapril; Female; Humans; Hypertension; Kidney Failure, Chronic; Kidney Function Tests; Male; Metabolic Clearance Rate; Middle Aged

The pharmacokinetics of spirapril and its active diacid metabolite spiraprilat were characterized in four groups of patients categorized on the basis of their renal function. No statistically significant effects of renal impairment upon the disposition of spirapril were detected. In contrast, there were significant perturbations in the pharmacokinetics of spiraprilat: The maximum plasma concentration (Cmax) values in the severely renally impaired group were 2-3 times those in the group of patients with normal renal function whereas the corresponding area under the curve (AUC) values were 5-6 times higher. However, there was no evidence of accumulation of spiraprilat in any of the groups as determined by the pharmacokinetic parameters derived after single and multiple doses. Thus, despite the evidence of a significant influence of renal impairment upon the disposition of spiraprilat, the lack of accumulation during the translation from single to multiple doses indicates that there is a considerable margin of safety for spirapril in renal impairment.

Topics: Angiotensin-Converting Enzyme Inhibitors; Creatinine; Enalapril; Humans; Hypertension; Kidney Diseases; Single-Blind Method

In this single-blind trial with a 2-week placebo run-in followed by a 4-week active-treatment period, patients were given 6 mg of spirapril once daily. Forty-nine hypertensive men and women were recruited; all had pretreatment diastolic blood pressures (DBP) of 95-115 mmHg with varying degrees of renal impairment. Regression analysis of pharmacokinetic parameters C(max)ss (the maximum steady-state drug concentration in plasma during a dosing interval), Cl/f (total plasma clearance) and k (elimination rate constant) of spirapril on creatinine clearance (Clcr) showed that the pharmacokinetics of spirapril were not significantly influenced by the degree of renal impairment. C(max)ss values of spiraprilat, however, increased with decreasing Clcr, and AUC(l)ss (area under the concentration-time curve during a dosing interval) values also increased. Regression analysis of the pharmacokinetic parameters C(max)ss, Clm/fm (total plasma clearance) and lambda 1 (rate constant of the first disposition phase) of spiraprilat on Clcr showed that Clm/fm as well as lambda 1 were linearly correlated with Clcr (p < 0.01). However, the results indicate that, even when renal elimination is completely blocked, there is significant elimination of spiraprilat through a non-renal pathway. In conclusion, the risk of drug accumulation after multiple dosing is minimal as the presence of a substantial non-renal spiraprilat elimination was consistently demonstrated.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Creatinine; Enalapril; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Regression Analysis; Single-Blind Method

In a randomized, double-blind, crossover study, 20 patients with mild to severe essential hypertension received 3 weeks of treatment with each of four dosages of spirapril (3, 6, 12 and 24 mg once daily) or placebo. Standing and supine blood pressures were measured by use of both an automatic oscillometric instrument (Dinamap) and a mercury sphygmomanometer over a 24-hour period. Spirapril at 6, 12 and 24 mg once daily produced similar reductions in systolic and diastolic blood pressure. At most time points, there was a statistically significant difference between the reductions with spirapril compared with placebo. Spirapril at 3 mg once daily was less effective than the higher dosages, producing a lower mean blood pressure reduction and a shorter duration of antihypertensive action, mainly as regards systolic pressure. Spirapril was well tolerated and no patients withdrew from the study because of adverse effects. These data suggest that, although all four evaluated spirapril dosages effectively lowered supine and standing blood pressure in patients with mild to severe hypertension, the blood pressure-lowering effect of the 3 mg/day regimen was less than optimal. There were only minor variations in efficacy between dosages > or = to 6 mg/day, which may be attributable to the variability of blood pressure. Further investigations of larger numbers of patients are required to verify these results.

Topics: Adolescent; Adult; Aged; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Blood Pressure Determination; Drug Administration Schedule; Enalapril; Female; Humans; Hypertension; Male; Middle Aged; Renin-Angiotensin System

The pharmacokinetics and haemodynamic effects of orally administered spirapril, a novel angiotensin-converting 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 micrograms.h.l-1, 923 micrograms.h.l-1 and 1300 micrograms.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.

Topics: Administration, Oral; Adult; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Chronic Disease; Enalapril; Female; Glycogen Storage Disease; Half-Life; Hemodynamics; Humans; Liver Cirrhosis; Liver Cirrhosis, Alcoholic; Liver Diseases; Male; Middle Aged; Pulse

A specific, sensitive and precise method for the simultaneous determination of spirapril (CAS 94841-17-5) and spiraprilat (CAS 83602-05-5) in human plasma is described. The method involves the use of enalapril as internal standard, solid-phase extraction, derivatization and capillary gas chromatography with mass sensitive detection. The working range is from 2.5 to 500 micrograms/l for spirapril and spiraprilat, respectively. Data demonstrating the precision and accuracy of the analytical method are given. Moreover, data concerning freeze-thaw stability, long-term stability of frozen samples, short-term stability of thawed samples, and stability of the extracts in the autosampler are given.

Topics: Angiotensin-Converting Enzyme Inhibitors; Enalapril; Freezing; Gas Chromatography-Mass Spectrometry; Humans; Indicators and Reagents; Reference Standards; Reproducibility of Results; Solutions

Spirapril is a prodrug that is converted by esterolysis to the active (but poorly absorbed) diacid spiraprilat. After intravenous infusion, the disposition of spirapril is monophasic with a terminal half-life of 20-50 minutes. Plasma clearance was 56 l/h and renal clearance was 11 l/h; the volume of distribution was 28 litres. After intravenous infusion of spiraprilat, the disposition was biphasic with half-lives of 2 hours and 35 hours, respectively. Plasma clearance of spiraprilat was 10 l/h, of which 7.6 l/h was cleared by the kidneys. The volume of distribution was 43 litres. The bioavailability of orally administered spirapril was 50% whereas the bioavailability of orally administered spiraprilat was virtually zero. There was a significant first-pass metabolism of spirapril after oral administration. The pharmacokinetics of spirapril were linear within the dose range of 6-50 mg whereas the disposition of spiraprilat was non-linear with respect to the terminal phase. Variability of the pharmacokinetic parameters of spiraprilat were significantly less than that of spirapril. Plasma concentrations of both spirapril and spiraprilat were increased by 30% in the elderly. Similarly, in patients with impaired liver function, plasma concentrations of spiraprilat were reduced by 30%. In patients with severe renal impairment, spiraprilat concentrations were significantly increased by a factor of 3-4. Spirapril showed no clinically relevant drug interactions with either glibenclamide, diclophenac, cimetidine, rifampicin, hydrochlorothiazide or nicardipine.

Topics: Adult; Age Factors; Aged; Angiotensin-Converting Enzyme Inhibitors; Dose-Response Relationship, Drug; Drug Interactions; Enalapril; Humans; Kidney Diseases; Liver Diseases; Reference Values

Radioimmunoassays for a nonsulfhydryl angiotensin converting enzyme inhibitor prodrug--spirapril--and its active metabolite--spiraprilate--are described. Nonextraction equilibrium assays using antibodies with a high specificity for spirapril or spiraprilate were used, with charcoal separation of bound and free tracer. Within-assay reproducibility (CV%) was less than 20% in the concentration range 0.5-40 micrograms/L for both analytes and the comparable value for between-assay reproducibility was less than 25%. Results for external quality control samples were in good agreement with the expected values of 0-250 micrograms/L (spirapril, r = 0.997) and 0-300 micrograms/L (spiraprilate, r = 0.999). Overall, samples circulated to four laboratories gave good agreement for measured values, including one center using gas chromatography-mass spectrometry analysis for the two compounds. Data are presented to show the suitability of these two assays to the measurement of spirapril and spiraprilate in clinical samples from assays to the measurement of spirapril and spiraprilate in clinical samples from dose-ranging and bioequivalence studies. Results are also shown relating drug plasma concentration data to a measurement of the pharmacodynamic effects of spiraprilate, namely inhibition of angiotensin converting enzyme activity. It is concluded that these assays have the sensitivity for use in studies to model the relationship between the pharmacokinetics and pharmacodynamics of the two compounds.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antibody Specificity; Buffers; Charcoal; Cross Reactions; Dextrans; Enalapril; Humans; Quality Control; Radioimmunoassay; Reference Standards; Serum Albumin, Bovine