COMPARISON OF THE PHARMACOKINETICS AND PHARMACODYNAMICS OF PERINDOPRIL, CILAZAPRIL AND ENALAPRIL

1. The pharmacokinetic and pharmacodynamic responses to enalapril, perindopril and cilazapril have been studied in essential hypertensives (2, 4 and 8 mg perindopril and 2.5 mg cilazapril, single dose and steady state) and normotensive volunteers (10 mg enalapril, single dose).
2. Plasma levels of the active diacid compounds reached similar peaks after single dose administration of the drugs. However, perindoprilat levels persisted for 5 days whereas cilazaprilat levels were not detectable beyond 12 h.
3. The higher levels of perindoprilat were associated with a greater inhibition of plasma angiotensin-converting enzyme (ACE) activity in both acute and steady state studies.
4. The potency of the active diacids in inhibiting plasma ACE activity was perindoprilat > cilazaprilat > enalaprilat.
5. There was a close relationship between plasma concentration, ACE inhibition and blood pressure decrease. Although both cilazapril and perindopril administration reduced blood pressure in hypertensive subjects, only perindopril exerted 24 h blood pressure control at the doses used.     

Pharmacokinetics of cilazapril during repeated oral dosing in healthy young volunteers

The pharmacokinetics of cilazapril and its active metabolite cilazaprilat in plasma were investigated in an open study of 13 healthy male volunteers, aged 18 to 43 years. One capsule containing 2.5 mg cilazapril was administered to each volunteer daily for 8 days. Plasma samples were obtained after the first and eighth doses. Concentrations of cilazapril, cilazaprilat and activities of angiotensin converting enzyme (ACE) were measured by radioenzymatic methods. For cilazapril, the values of apparent plasma clearance (about 15 l/h) and volume of distribution (around 28 l) were sufficiently high to suggest that significant pre-systemic hydrolysis to cilazaprilat occurred. There were no significant changes in these values after repeated dosing. There were small, but statistically significant, increases in mean peak concentrations, mean areas under concentration-time curves and mean trough concentrations from the first to the eighth dose. A steady state was achieved after eight doses with an accumulation of 20-30%. The mean effective half-life was approximately 9 h. Despite the accumulation of cilazaprilat in plasma, there were no significant differences in plasma ACE inhibition from the first to the eighth dose.     

Initial and steady state pharmacokinetics of cilazapril in congestive cardiac failure.

Twenty one patients with NYHA class II-III congestive heart failure received single ascending doses of 0.5, 1.25 and 2.5 mg cilazapril daily followed by the minimum effective dose for six weeks. Fifteen patients completed the study, but the data from only 11 were sufficiently complete for kinetic evaluation. The pharmacokinetics of the metabolite, cilazaprilat, after a single dose of 0.5 mg cilazapril were similar to previous observations in healthy volunteers at identical dosage. Repeat administration, however, led to greater accumulation than previously observed in volunteers at the higher dosages of 1.25 or 5 mg given for 8 days. Seven patients experienced adverse events. Four were severe, leading to withdrawal of the patients from the study, but only one event was related to cilazapril. Of the other three, one suffered a myocardial infarction and subsequently died due to worsening congestive heart failure. One other patient was withdrawn with two adverse events probably related to cilazapril. No other deaths occurred amongst the study population, and there were no significant abnormalities in haematology or blood chemistry.     

Pharmacokinetics and haemodynamic effects of the angiotensin converting enzyme inhibitor cilazapril in hypertensive patients with normal and impaired renal function

1 The pharmacokinetic and pharmacodynamic properties of the angiotensin converting enzyme (ACE) inhibitor cilazapril were studied in 30 hypertensive patients with various degrees of renal function.
2 After a single oral dose, apparent cilazaprilat clearance was dependent on renal function being 16.0±3.0, 11.1 ± 3.0, 8.7 ± 3.7 and 6.7 ± 2.1 l h^-1 (means ± s.d.) in patients with creatinine clearances (CL_cr) of > 100, 41-100, 21-40, and 8-20 ml min^-1, respectively.
3 During 11 weeks of treatment with cilazapril, doses were adjusted to the CL_cr and varied from 0.5 to 5.0 mg once daily. At 24 h after drug administration a clear antihypertensive response was seen only in the low clearance groups (CL_cr < 40ml min^-1). In contrast, and despite higher once daily dosages, the decline of mean arterial pressure was small and cilazaprilat concentrations after 24 h were lower in the high clearance groups.
4 This study demonstrates that chronic once daily treatment with cilazapril is effective in patients with impaired renal function at dosages adjusted to creatinine clearance. No accumulation was seen. Since cilazaprilat clearance was high in the high creatinine clearance groups, a clear antihypertensive response in these groups was only seen at 3 h after drug administration.     

Pharmacokinetics of the converting enzyme inhibitor cilazapril in normal volunteers and the relationship to enzyme inhibition: development of a mathematical model

The pharmacokinetics of the new converting enzyme inhibitor cilazapril were investigated in 12 healthy male volunteers. Single oral doses of 1.25, 2.5, 5, and 10 mg of cilazapril were tested in groups of six subjects, each of whom received two different doses. A 2-week interval was allowed between treatments. Plasma levels of cilazaprilat, the active form of cilazapril, were measured for up to 3 days after drug administration. Peak plasma levels and 24-h areas under the curve (AUCs) were almost directly proportional to dose, and the elimination half-life (t1/2) during the first 8 h after dosing was 1.5 h. From 24 h on, there was a prolonged terminal phase with a t1/2 of approximately 50 h, and there was only slight dose-dependency during this phase. These data suggest that the pharmacokinetics of cilazapril are nonlinear. A physiologically realistic model based on saturable binding to converting enzyme was developed to account both for the drug kinetics and for the relationship of the kinetics to the dynamics of plasma converting enzyme inhibition. A number of conclusions relevant to the therapeutic application of cilazapril in hypertension are drawn from the data and from the pharmacokinetic-pharmacodynamic model.     

A comparison of the pharmacokinetics and pharmacodynamics of cilazapril between Chinese and Caucasian healthy,normotensive volunteers

Methods: The pharmacokinetics and pharmacodynamics of the angiotensin converting enzyme (ACE) inhibitor cilazapril were studied in 12 Chinese and 13 Caucasian, healthy, normotensive volunteers on their normal diet. Cilazapril was given orally as a single 2.5 mg capsule. Plasma was sampled for assay of the active metabolite, cilazaprilat, plasma renin activity (PRA), aldosterone, angiotensin I (AI) and ACE-activity. Plasma concentrations of the active drug were measured by radioimmunoassay. Blood pressure and heart rate were measured at regular intervals. Results: The pharmacokinetic parameters of cilazaprilat were similar in the two ethnic groups. No significant difference in plasma concentrations was found at any of the time points. However, the weight-adjusted plasma clearance was significantly higher in the Chinese group, which is compatible with their lower body weight. The effects on plasma hormones were also comparable, although there was a somewhat greater rise in PRA and greater fall in aldosterone levels in Chinese than in Caucasians. The effect of cilazapril on blood pressure and heart rate was greater than was previously reported in healthy volunteers. Systolic (SBP) and diastolic (DBP) blood pressure were significantly reduced in both groups, but there was a more prolonged reduction in DBP in Caucasians. In addition, heart rate (HR) was significantly increased from baseline from 5 h onwards in Chinese subjects and significantly higher in comparison with Caucasians at most time points from 1.5 h onwards. The pharmacokinetic parameters of cilazapril were essentially the same in healthy, normotensive Chinese and Caucasians. Cilazapril reduced blood pressure acutely in both groups, with good tolerance. The inhibition of ACE in relationship to time and the plasma concentrations of cilazaprilat were similar in the two groups, although the changes in PRA and aldosterone suggest an ethnic difference in the responses of the renin-angiotensin-aldosterone system. Received: 24 January 1995/Accepted in revised form: 18 September 1995     

Cilazapril. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in cardiovascular disease.

Cilazapril is an orally active angiotensin converting enzyme (ACE) inhibitor which lowers peripheral vascular resistance without affecting heart rate. Like enalapril and ramipril it is a prodrug, and is hydrolysed after absorption to cilazaprilat, which has a long terminal phase elimination half-life permitting once daily administration. Given once daily at doses between 2.5 and 5 mg, cilazapril reduces arterial blood pressure in patients with mild to moderate essential and renal hypertension. Patients who do not respond adequately to cilazapril monotherapy usually respond with the addition of a diuretic such as hydrochlorothiazide. Preliminary data suggest that cilazapril is of comparable antihypertensive efficacy to usual therapeutic dosages of hydrochlorothiazide, slow release propranolol, nitrendipine, captopril and enalapril. In small studies cilazapril has produced sustained beneficial haemodynamic effects in patients with congestive heart failure. Cilazapril has been well tolerated and exhibits tolerability typical of ACE inhibitors as a class, including their lack of detrimental effect on glucose or lipid metabolism. Cilazapril should provide an effective alternative in the treatment of hypertension and, if preliminary data are confirmed, in congestive heart failure.     

Repeated administration of the converting enzyme inhibitor cilazapril to normal volunteers

Cilazapril 1.25 and 5.0 mg p.o. q.d. was administered in double-blind fashion to two groups of six normal volunteers on 8 consecutive days. Blood pressure, heart rate, and plasma converting enzyme activity were measured each day prior to drug administration and up to 72 h after the last dose. Plasma renin activity, blood angiotensin I, plasma angiotensin II, and aldosterone as well as plasma cilazaprilat levels were determined on the first and the last day of active treatment at times 0, 4, and 24 h. The drug was very well tolerated by all volunteers. At 4 h postdrug, plasma converting enzyme activity was reduced in dose-dependent fashion on the first and the eighth day; plasma cilazaprilat levels were also clearly dose dependent. Nevertheless, 24 h postdrug cilazaprilat levels were similar on the first and last day of drug administration, and plasma converting enzyme activity was also stable throughout the 8 days. The various components of the renin-angiotensin system responded in the usual fashion. These results provide strong evidence that cilazapril is a very potent and highly effective converting enzyme inhibitor. Doses well below 5 mg/day will probably suffice for therapeutic efficacy. These data also confirm the hypothesis formulated in the preceding article, i.e., that there is no accumulation of the drug with repeated administration despite its long pharmacological half-life (t1/2).     

A method for estimating the potency of angiotensin-converting enzyme inhibitors in man.

Dose-response curves of the effect of angiotensin I (A-I) infusion on diastolic blood pressure were constructed before and 3 h following single oral doses of the angiotensin-converting enzyme (ACE) inhibitor cilazapril (1.25 to 30 mg) in six normal male subjects. Cilazapril shifted the A-I dose-response curves dose dependently rightward; Schild-plot analysis indicated a competitive antagonism by cilazapril with an apparent Ki-dose of about 0.6 mg.     

Hemodynamic responses to angiotensin I in normal volunteers and the antagonism by the angiotensin-converting enzyme inhibitor cilazapril

According to classic pharmacologic theory, agonist/antagonist competition can be used to quantify an antagonist's potency by measurement of agonist dose-response curves in the presence of varying doses of the antagonist. We used this principle to characterize the interaction between angiotensin I (AI) and the angiotensin-converting enzyme (ACE) inhibitor cilazapril in humans. In addition, by comparing the effects of AI and angiotensin II before and after administration of a 30-mg dose of cilazapril, we could show the specific AI antagonism of the ACE inhibitor in humans. To obtain the antagonist's dose-response curves, six healthy male volunteers received five single oral doses of cilazapril, 0.5-8.0 mg. Enalapril, 10 mg, and captopril, 12.5 mg, served as positive controls and placebo as the negative control. Dose-response curves following intravenous infusions of AI were established 4 h after oral ingestion of the ACE inhibitors. Noninvasively measured systolic and diastolic blood pressures and total peripheral resistance assessed AI effects. Cilazapril dose dependently shifted the AI dose-response curve rightward, with 1.0 mg inducing a twofold shift. Enalapril and captopril appear less potent, on a milligram basis, in antagonizing AI effects 4 h after drug intake. The methodology could be a useful tool for a rational testing and comparison of ACE inhibitors in clinical pharmacology.     

Pharmacokinetics of intravenous cilazaprilat in normal volunteers.

The pharmacokinetics of 1 mg, 2 mg and 4 mg of cilazaprilat administered intravenously were determined in a group of eight volunteers. The fall in plasma concentration was polyphasic. Elimination was predominantly by renal excretion of the unchanged drug. The mean renal clearance values following 1 mg, 2 mg and 4 mg doses were 5.3 +/- 0.5, 8.1 +/- 0.5, and 9.8 +/- 0.5 l h-1 and plasma clearances were 7.8 +/- 0.5, 10.4 +/- 0.5 and 11.8 +/- 0.6 l h-1, respectively. Thus, plasma and renal clearances were dose dependent. ACE inhibition was greater than 82% for the first 4 h and about 55% at 24 h, after all three doses. There were no significant haemodynamic effects at any dose.     

A comparison of the efficacy of cilazapril versus cilazapril plus hydrochlorothiazide in patients with mild to moderate essential hypertension

Summary The efficacy of cilazapril monotherapy and in combination with hydrochlorothiazide 12.5 mg was compared in a multicentre, double blind, randomised parallel group study in 87 patients with mild to moderate essential hypertension over 8 weeks. After a 2 week single blind placebo run-in period, patients received either 2.5 mg cilazapril or 2.5 mg cilazapril plus 12.5 mg hydrochlorothiazide once daily. At Week 4 the cilazapril dose was increased from 2.5 mg to 5.0 mg if the mean sitting diastolic blood pressure was greater than 90 mmHg or had not decreased by more than 10 mmHg.After 8 weeks treatment 72% of patients responded to 2.5 mg cilazapril increasing to 88% with cilazapril 5.0 mg. For cilazapril plus hydrochlorothiazide, 83% responded to 2.5 mg cilazapril increasing to 96% on 5.0 mg cilazapril.The high response rate to low dose cilazapril monotherapy and hydrochlorothiazide combination therapy has important implications for minimising the cost of therapy with ACE inhibitors.Inhibace General Practice Study Group: Drs. Atkinson, Bevin, Choy, DeLacey, Dine, Doerr, Dykes, Eames, Edwards, Ford, Gare, Haycock, Haywood, Hendy, Hunter, Loan, Lowe, Mules, Nealie, Parker, Pollock, Rasalingham, Reekie, Richmond, Sandin, Staub, Suckling, Surynt, Vickers, Wellington, Wells, Wong and Young     

Antihypertensive effects of cilazapril, 2.5 and 5 mg, once daily versus placebo on ambulatory blood pressure following single- and repeat-dose administration.

Ambulatory blood pressure (ABP) monitoring was used to evaluate the 24-h antihypertensive efficacy of single- and repeat-dose administrations of the nonsulfhydryl-converting enzyme inhibitor cilazapril, 2.5 and 5 mg, versus placebo in patients with mild to moderate essential hypertension. After a 2-week placebo run-in period, patients were randomized to receive, in a double-blind procedure, either 2.5 mg cilazapril (n = 14), 5 mg cilazapril (n = 14), or placebo (n = 14) for 4 weeks. In calculating the systolic/diastolic blood pressure (BP) trough-to-peak (T/P) ratio after subtraction of the placebo effect, 5 mg cilazapril appeared to be more effective than 2.5 mg cilazapril following single- (59/54% vs. 21/48%) and repeat-dose administration (47/76% vs. 31/49%). There were significant differences in 24-h and awake ABP for both 2.5 and 5 mg cilazapril as compared to placebo after single- and repeat-dose administrations. However, there were no significant differences in 24-h and awake ABP reduction between 2.5 and 5 mg cilazapril after single- and repeat-dose administrations. Furthermore, the percentages of "BP load" were identical with both regimens after the first dose (46 vs. 43%) and at steady-state (37 vs. 29%). These data demonstrate that 2.5 and 5 mg doses of cilazapril have equivalent antihypertensive efficacy using ABP and that 24-h ABP monitoring should also be performed in dose-response studies.     

Antihypertensive effects and pharmacokinetics of single and consecutive doses of cilazapril in hypertensive patients with normal and impaired renal function

The antihypertensive effects and pharmacokinetic properties of cilazapril, a long-acting angiotensin-converting enzyme (ACE) inhibitor, were investigated in hypertensive patients with normal renal function (NRF; n = 5) and those with impaired renal function (IRF; n = 7). A 1.25-mg dose of cilazapril was administered orally once a day for 5 or 8 days. Measurement of blood pressure and sampling of blood specimens were done on the first and last days of treatment. Cilazapril induced significant falls in systolic and diastolic blood pressures as early as 1 h after administration. The antihypertensive effects were still present at 24 h postdose. Serum ACE activity was markedly suppressed over 24 h, with the enzyme inhibition greater in the IRF group. Plasma levels of the active diacid in the IRF group were higher than those in the NRF group, with significant differences in the peak levels and areas under the curve (AUC). A significant inverse correlation was found between the creatinine clearance and the AUC for the diacid. Cilazapril was well tolerated by all the patients, and no adverse reactions were observed. These results suggest that cilazapril has a long-lasting action and that it is a useful antihypertensive agent for controlling blood pressure in patients with either NRF or IRF.     

The pharmacodynamics and dose-response relationships of the angiotensin converting enzyme inhibitor, cilazapril, in essential hypertension.

In a double-blind, placebo controlled, crossover study 12 patients with essential hypertension received single doses of 5, 10 and 20 mg of cilazapril, a new angiotensin converting enzyme (ACE) inhibitor. All doses similarly and significantly (P less than 0.05) reduced supine and erect blood pressure without increasing heart rate. The hypotensive effect was evident within 1 h, maintained for up to 8 h, with a maximal effect at 6 h. There was no discernible effect on blood pressure at 24 h after dosing. Plasma ACE activity was markedly inhibited to the same extent after all doses, with a peak inhibition of 94-96% at 2-3 h. At 24 h residual inhibition of ACE was 49-54%. Plasma renin activity increased in a dose-dependent manner with a peak at 6 h, and returned to baseline at 24 h. No correlation was found between the reduction in blood pressure and plasma renin activity, either at baseline or following cilazapril. There were no significant changes in plasma noradrenaline and the responses to upright posture and to dynamic exercise were preserved. There was no evidence of impaired exercise performance. Cilazapril is a potent ACE inhibitor with a rapid onset and a prolonged duration of action. These results suggest that peak ACE inhibition is achieved by 5 mg and that lower doses may be useful in clinical practice.     

Cilazapril and enalapril inhibit local angiotensin I conversion in human veins but lack direct venodilating properties

We studied the angiotensin-converting enzyme (ACE)-dependent and ACE-independent (direct) effects of two ACE inhibitors, cilazaprilat and enalaprilat, in 12 healthy human subjects. The dorsal hand vein compliance technique was used because venous constriction and relaxation, independent of reflex responses and systemic ACE inhibition, can be measured by local infusions of very small amounts of drugs. Angiotensin I (dose range 6-1,550 ng/min) was infused alone or coinfused with cilazaprilat or enalaprilat (dose range 7.8-3,900 ng/min). In separate experiments, cilazaprilat or enalaprilat (dose range 3.9-31 micrograms/min), or prostaglandin I2 (PGI2, dose range 0.13-32 ng/min) was infused into veins that had been submaximally preconstricted with phenylephrine. Angiotensin I caused a marked venoconstriction limited by rapid tachyphylaxis. At doses greater than 78 ng/min, cilazaprilat and enalaprilat completely inhibited angiotensin I-induced venoconstriction. This inhibition was reversible after 14-31 min, suggesting an inhibition of ACE associated with the vein wall. Infusions of cilazaprilat or enalaprilat had no effect on the diameter of the vein at rest or after submaximal preconstriction with phenylephrine. In contrast, exogenous PGI2 was a potent venodilator in our system. We conclude that cilazaprilat and enalaprilat are inhibitors of ACE associated with the vein wall, but there is no evidence for either drug of direct, ACE-independent, prostaglandin-mediated vasodilation.     

The effect of oral cilazapril and prazosin on the constrictor effects of locally infused angiotensin I and noradrenaline in human dorsal hand veins.

The effects of the ACE inhibitor cilazapril (5 mg p.o.) and the alpha 1-adrenoceptor blocker prazosin (2 mg p.o.) were investigated on the dose-response curves to angiotensin I and to noradrenaline, administered locally in the hand veins in six healthy male volunteers in doses not producing systemic effects. Both angiotensin I and noradrenaline produced a dose-dependent constriction of the congested veins. The angiotensin I effects were completely abolished after the administration of cilazapril but not significantly altered after the administration of prazosin. The noradrenaline dose-response curves were shifted to the right (dose ratio about 10) by prazosin, but not by cilazapril. The data suggest that angiotensin I, after having been converted to angiotensin II exerts direct venoconstrictor effects which under resting conditions are not mediated by noradrenaline release.     

Effects of single doses of the converting enzyme inhibitor cilazapril in normal volunteers

The new converting enzyme inhibitor cilazapril, or RO 31-2848, was evaluated in 14 healthy male volunteers. In a pilot study in two subjects, the inhibiting capacity of single oral doses of 5 and 10 mg on the pressure and heart rate response to exogenous angiotensin I was assessed. Both doses reduced the blood pressure response to angiotensin I to 10% of control within 45 min and for the 4 h tested. In the main study, 12 volunteers each received two single oral doses of cilazapril at a 2-week interval, and plasma converting enzyme and renin activity, blood angiotensin I, plasma immunoreactive angiotensin II and aldosterone were measured serially. Single doses of 1.25, 2.5, 5, and 10 mg of cilazapril were tested in groups of six subjects each. All doses inhibited plasma converting enzyme activity by 90% for at least 8 h and induced the expected pattern of changes of the renin-angiotensin-aldosterone system. Only slight dose-dependent variations in the effect were observed. Basic heart rate and blood pressure were not altered by any of the doses, which all were well tolerated. These data suggest that cilazapril is a very potent and long-acting new converting enzyme inhibitor.     

Adaptive changes in the acute haemodynamic effects of cilazapril during chronic treatment Comparison with long-term clinical effect

Objective: To study the adaptive changes in the acute haemodynamic response to ACE inhibition during chronic treatment in CHF. Methods: The acute and chronic effects of oral cilazapril (CLZ) treatment, an ACE-inhibitor with prolonged duration on haemodynamic measures (PCWP, PAP, RAP, CI and SVR) and clinical parameters (Quality-of-Life and NYHA class) were investigated in a double-blind, randomised, placebo-controlled trial in CHF. One hundred and thirty five patients (112 completing) in NYHA Classes II-III, on digitalis and diuretic treatment, were randomised after 2 weeks of placebo run-in, to receive either placeabo or CLZ 0.5 mg, 1.0 mg or 2.5 mg daily for 12 weeks, followed by 2 week placebo wash-out. Haeamodynamic studies, including exercise tests before and 3 h after medication, were performed on the first and last days of treatment. Measurements were performed at rest and at the maximum exercise level. Results: In ACEI-naive patients oral CLZ 0.5 and 1 mg/d caused a dose dependent decrease in PCWP and diastolic PAP, and a significant reduction of SVR mg. A slight increase in CI was observed in all groups. The maximum effect was observed 3–5 h post dose. After 12 weeks of oral treatment, the acute response was similar but was attenuated relative to the first dose. Exercise tolerance improved in a dose dependent manner. The NYHA classification remained unchanged or improved in the majority of patients. Entry into the 2.5 mg group had to be terminated at an early stage due to severe adverse events observed after the first dose. Conclusion: During chronic treatment, the haemodynamic response to oral cilazapril was attenuated, indicating that continued clinical improvement in patients with CHF on CLZ is independent of to its acute haemodynamic effects. Received: 21 August 1995/Accepted in revised form: 2 January 1996     

Pharmacokinetics and pharmacodynamics of zofenopril in healthy volunteers

This study was carried out to investigate the pharmacokinetics of zofenopril (CAS 81938-43-4) and zofenoprilat, the behaviour of the angiotensin converting enzyme (ACE) (pharmacodynamics) following the administration of zofenopril calcium at the single oral dose of 60 mg in eighteen healthy volunteers. This open label, one-way study was carried out in a single centre on 18 healthy volunteers. The volunteers received an oral single 60 mg dose of zofenopril calcium following an overnight fast. The tablet was swallowed with 250 ml of water. Fasting continued for additional 4 h after dosing and no other liquid intake was allowed from 1 h before to 2 h after administration. Plasma concentrations of zofenopril and its active metabolite zofenoprilat as well as serum ACE activity were measured before drug intake (baseline) and on timed samples over a 36 h period after dosing by LC-MS-MS, a highly sensitive, validated method for active moiety concentrations. Peak plasma concentration was reached on average at 1.19 h with zofenopril and at 1.36 h with zofenoprilat. Concentrations then decreased reaching values under or close to the limit of quantitation (1 ng.ml-1 for zofenopril, 2 ng.ml-1 for zofenoprilat) from 8 to 16 h after dosing. Complete inhibition of ACE was seen at the first blood sampling time (1 h) and lasted on average up to 9.44 h. ACE activity then slowly reactivated, but enzyme inhibition continued and was estimated to be 74% and 56% at 24 and 36 h following drug administration, respectively. From these data a complete or almost complete enzyme inhibition is expected with zofenopril given in repeated dose regimen.