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PubMedDate not supplied

Disposition of enalapril and its diacid metabolite, enalaprilat, in a perfused rat liver preparation. Presence of a diffusional barrier for enalaprilat into hepatocytes.

Enalaprilat (MK-422), a new and potent angiotensin- converting enzyme inhibitor, and its monoethyl ester precursor, enalapril, were studied in a single pass perfused rat liver preparation under constant perfusate flow (10 ml/min) at concentrations of 0.29-0.41 microM for 14C-enalapril and 0.01-0.015 microM for 3H- enalaprilat . During their simultaneous delivery to the same rat liver preparation, the steady state hepatic extraction ratio of 14C-enalapril was high (0.861 +/- 0.02) and 14C- enalaprilat appeared rapidly in effluent perfusate plasma. Of the enalapril dose, 22.7 +/- 6.9% appeared in bile. 14C- Enalaprilat accounted for 79% of the total radioactivity in bile (18% of dose) whereas 14C-enalapril was present only as 10% of the total (2.3% of dose). By contrast, the steady state hepatic extraction of 3H- enalaprilat was very low (0.053) and the disappearance was virtually identical to the appearance of 3H- enalaprilat in bile. These findings suggest that diffusional barrier exists for enalaprilat as the preformed metabolite, which hinders penetration into hepatocytes, and therefore, elimination. The precursor, enalapril, effectively brings enalaprilat into hepatocytes were more extensive biliary excretion of the generated metabolite takes place. This account adds to our further understanding of metabolite kinetics; in addition to the uneven distribution of enzyme system and the intrinsic clearance for metabolite formation and elimination, the presence of a diffusional barrier is another important determinant which may cause deviations between the kinetics of a generated and performed metabolite.

Animals↗
PubMed1989

Intravenous enalaprilat and autonomic reflexes. The effects of enalaprilat on the cardiovascular responses to postural changes and tracheal intubation.

Thirty healthy patients, who were to undergo surgery which required tracheal intubation, were given an intravenous injection of enalaprilat (either 0.5 mg, 1 mg, 2 mg or 4 mg; six patients for each dose) or normal saline 17 minutes before induction of anaesthesia with thiopentone 3-5 mg/kg, and suxamethonium 1.5 mg/kg. Postural manoeuvres were performed 5 minutes before and 6, 11 and 16 minutes after enalaprilat or saline. Complete inhibition of angiotensin converting enzyme occurred with all doses of enalaprilat, which allowed the four different treatment groups to be considered as one large treated group. The mean arterial pressure was almost unchanged during the postural manoeuvres; the heart rate increased, mostly similarly (by approximately 10%) in both groups. Mean arterial pressure in the recumbent position decreased over the 17 minutes before induction in the enalaprilat group, and increased slightly in the control group (treated mean, -5.0%; controls mean, 1.8%; difference, -6.8%; 95% confidence intervals of difference, -2.3 to -11.3%, p less than 0.01). This difference was again seen after induction (treated, -8.0%; controls, 7.7%; confidence intervals of difference, -0.6 to -31%) and for a 5-minute period shortly after tracheal intubation. The increases in mean arterial pressure produced by intubation itself were similar in both groups (treated, + 36%; controls, + 35%; 95% confidence intervals of difference, -16% to + 18%). Changes in heart rate after induction were also similar in both groups. It is concluded that intravenous enalaprilat acted as a hypotensive agent with a sparing effect on autonomic reflexes, both before and after induction of anaesthesia.

Adult↗
PubMed1993

Formed and preformed metabolite excretion clearances in liver, a metabolite formation organ: studies on enalapril and enalaprilat in the single-pass and recirculating perfused rat liver.

Single-pass and recirculating rat liver perfusion studies were conducted with [14C]enalapril and [3H]enalaprilat, a precursor-product pair, and the data were modeled according to a physiological model to compare the different biliary clearances for the solely formed metabolite, [14C]enalaprilat, with that of preformed [3H]enalaprilat. With single-pass perfusion, the apparent extraction ratio (or biliary clearance) of formed [14C]enalaprilat was 15-fold the extraction ratio of preformed [3H]enalaprilat, an observation attributed to the presence of a barrier for cellular entry of the metabolite. Upon recirculation of bolus doses of [14C]enalapril and [3H]enalaprilat, the biliary clearance, estimated conventionally as metabolite excretion rate/midtime metabolite concentration, for formed [14C]enalaprilat was again 10- to 15-fold higher than the biliary clearance for preformed [3H]enalaprilat, but this decayed with perfusion time and gradually approached values for preformed [3H]enalaprilat. The decreasing biliary clearance of formed enalaprilat with recirculation was explained by the dual contribution of the circulating and intrahepatic metabolite (formed from circulating drug) to excretion. Physiological modeling predicted (i) an influx barrier (from blood to cell) at the sinusoidal membrane as the rate-limiting process in the overall removal of enalaprilat, (ii) a 15-fold greater extraction ratio or biliary clearance for formed [14C]enalaprilat over [3H]enalaprilat during single-pass perfusion, and (iii) the time-dependent and declining behaviour of the biliary clearance for formed [14C]enalaprilat during recirculation of the medium. In the absence of a direct knowledge of eliminating organs in vivo, this variable pattern for excretory clearance of the formed metabolite within the organ is indicative of a metabolite formation organ.

Animals↗
PubMed1989

Renal handling of enalapril and enalaprilat: studies in the isolated red blood cell-perfused rat kidney.

An isolated recirculating or single pass red cell-perfused rat kidney preparation (IPK) was used to examine the differential handling of renal metabolites. In single pass experiments, enalapril was primarily metabolized to its polar, dicarboxylic acid metabolite, enalaprilat, and its fractional excretion (FE) was less than unity, suggesting net reabsorption. Its steady-state extraction ratio decreased from 0.3 to 0.2 at concentrations of 1.06 to 12.7 microM, due to a saturation of enzymes for esterolysis. Enalaprilat administered to the IPK was excreted into urine in a concentration-independent (0.41-35.3 microM) fashion, with FE values approximating unity, suggesting net filtration. Differences in handling were observed for enalaprilat, as a metabolite formed from enalapril and as an administered (preformed) species in the single pass IPK, when tracer concentrations of [14C]enalapril and [3H]enalaprilat were given simultaneously. A comparison made between steady-state extraction ratio Ess[mi] [generated metabolite]/glomerular filtration rate (GFR) and Ess[pmi] [preformed metabolite]/GFR, respectively, revealed a 2-fold difference. The finding suggests the presence of a barrier for entry of enalaprilat into the kidney. Or else, in absence of the barrier, the opposite would be observed, that is, Ess [pmi]/GFR greater than Ess [mi]/GFR because preformed enalaprilat, in contrast to generated enalaprilat, undergoes filtration and utilizes facilitative transport carriers at the basolateral membrane. In recirculating IPKs which received simultaneously a tracer bolus dose of [14C]enalapril and [3H]enalaprilat, the FE values for generated [14C]enalaprilat were high and variable, decreasing with perfusion time and exceeding those for preformed [3H]enalaprilat, which approached unity with perfusion time. The variable FE values for [14C]enalaprilat are due to time-dependent contributions of circulating enalaprilat (which behaves identically to preformed enalaprilat) and the intrarenally generated enalaprilat. Hence, with renal drug metabolism, the conventional method of estimating urinary clearance (or Fe[mi]) for the metabolite [(total) excretion rate/midpoint plasma FE[mi] metabolite concentration] results in a greater metabolite clearance than that predicted from the administration of preformed metabolite.

Animals↗
PubMed1994

Cardiopulmonary actions of intravenously administered enalaprilat in trauma patients.

OBJECTIVE: To determine the cardiopulmonary actions of the intravenous administration of the angiotensin-converting enzyme inhibitor enalaprilat in hypertensive trauma patients. DESIGN: Prospective, before/after trial. SETTING: Intensive care unit (ICU) of a university hospital. PATIENTS: Twenty critically injured and hypertensive ICU patients. All patients were receiving continuous sedation (fentanyl and midazolam) for at least 2 days before the injection of enalaprilat and had a mean arterial pressure (MAP) of > 95 mm Hg. "Responders" were defined as having a decrease in MAP of > 15% within 30 mins after enalaprilat injection. INTERVENTIONS: Intravenous administration of 0.06 mg/kg of the angiotensin-converting enzyme inhibitor enalaprilat. Repeated doses were given when no sufficient response (decrease of MAP of > 15% within 30 mins after injection) was seen ("nonresponders"). MEASUREMENTS: In addition to standard hemodynamic monitoring, right ventricular hemodynamics and oximetric variables were also documented. Measurements were carried out before enalaprilat injection (during hemodynamic steady state [baseline values]) and at 1, 5, 10, 20, 30, 60, and 120 mins after enalaprilat administration. MAIN RESULTS: MAP was successfully controlled in 17 of 20 patients (maximum decrease -27 mm Hg [-26%]). In the three other patients, even reinjection of enalaprilat (0.06 mg/kg) did not sufficiently reduce MAP. In the 17 responders, heart rate did not increase, whereas central venous pressure, pulmonary arterial pressure, and pulmonary artery occlusion pressure decreased significantly after intravenous administration of enalaprilat. Cardiac index changed only slightly (mean maximum +0.70 L/min/m2 [+18%]). Right ventricular ejection fraction increased from 36% to 45% (p < .05); right ventricular end-diastolic and end-systolic volume index decreased significantly. Both systemic and pulmonary vascular resistance indices decreased within the investigation period (-31% and -16%, respectively). Pao2/FIO2, intrapulmonary right-to-left shunting, and oxygen extraction ratio were not altered. Oxygen delivery index (+17%) and oxygen consumption index (+20%) increased during the investigation period (p < .04). CONCLUSIONS: The intravenous administration of enalaprilat successfully decreased blood pressure in most of our patients. Mechanisms other than the renin-angiotensin system also appear to be involved in hypertensive, critically ill patients. Pulmonary function was not altered; right ventricular function, and both oxygen consumption and oxygen delivery improved in the enalaprilat responder group. Thus, the availability of intravenous enalaprilat seems to enlarge our armamentarium for treating hypertension in the critically ill patient.

Acute Disease↗
PubMed1995

Cardiorespiratory effects of continuous i.v. administration of the ACE inhibitor enalaprilat in the critically ill.

1. Cardiorespiratory effects of long-term, continuous i.v. administration of the ACE inhibitor enalaprilat were studied. 2. Forty-five consecutive critically patients suffering from trauma or postoperative complications were randomly separated into three groups (15 patients in each group) receiving either 0.25 mg h-1 or 0.50 mg h-1 enalaprilat, respectively, or saline solution as placebo (= control group). The infusion was continued for 5 days. 3. Haemodynamic and respiratory parameters were intensively monitored on admission to the intensive care unit (= 'baseline' values) and daily during the next 5 days. 4. Mean arterial blood pressure (MAP) decreased significantly only in the enalaprilat-treated patients, whereas heart rate (HR) remained unchanged in these patients. 5. Pulmonary capillary wedge pressure (PCWP) and pulmonary artery pressure (PAP) were decreased by enalaprilat (0.50 mg h-1: PAP (mean +/- s.d.) decreased from 28.0 +/- 4.1 to 24.0 +/- 3.0 mm Hg) and remained significantly lower than in the control group. In the untreated control group, cardiac index (CI), oxygen consumption (VO2I) and oxygen delivery (DO2I) significantly decreased, which was blunted by enalaprilat infusion. Oxygen extraction (O2-extr) increased in both enalaprilat groups (0.25 mg h-1: from 26.1 +/- 5.5 to 30.4 +/- 4.0%; 0.50 mg h-1: 25.2 +/- 5.6 to 30.9 +/- 4.4%) and decreased in the control patients. 6. Right ventricular haemodynamics improved by enalaprilat infusion (0.50 mg h-1: RVEF increased from 40.0 +/- 3.5 to 45.5 +/- 4.0%). Lactate plasma concentrations decreased in the group with 0.50 mg h-1 enalaprilat (from 1.9 +/- 1.0 to 1.3 +/- 0.3 mg dl-1) and increased in the control patients. 7. Continuous infusion of the ACE inhibitor enalaprilat exerted beneficial cardiorespiratory effects in the critically ill. The widespread common risk of altered perfusion with decreased CI, DO2, VO2, O2-extr and increased lactate concentration was blunted by enalaprilat infusion. 8. Although 0.5 mg h-1 enalaprilat was most effective, a dose of 0.25 mg h-1 also showed beneficial haemodynamic effects in the critically ill.

Adult↗
PubMed2005

Pharmacokinetics and pharmacodynamics profiles of enalapril maleate in healthy volunteers following determination of enalapril and enalaprilat by two specific enzyme immunoassays.

BACKGROUND AND OBJECTIVES: Most of the pharmacokinetic (PK) parameters for enalapril and enalaprilat were established following determination of the drug and its metabolite, using angiotensin converting enzyme (ACE) inhibition assays. In these methods, enalapril has to be hydrolysed to enalaprilat first and then assayed. The purpose of this study was to re-estimate the PK parameters of enalapril and enalaprilat in healthy volunteers using two specific enzyme immunoassays for enalapril and enalaprilat. METHODS: The rate and extent of absorption of enalapril and enalaprilat from a 10-mg dose of two enalapril maleate commercial brands (Renetic and Enalapril) were estimated using a two-way-cross over design with 1-week washout period. Blood pressure was also measured at specified time intervals and correlated to enalaprilat plasma concentrations. RESULTS: For enalapril, the AUC(o-->infinity) values (Mean+/-SD) were 450.0+/-199.5 and 479.6+/-215.6 ng h/mL, Cmax values were 313.5+/-139.6 and 310.1+/-186.6 ng/mL, Tmax values were 1.06+/-0.30 h and 1.13+/-0.22 h, and t1/2 ranged between 0.3 to 6.1 h (1.6+/-1.5) and 0.40 to 5.05 h (1.3+/-1.0), for the two brands. For enalaprilat, the AUC(o-->infinity) values were 266.9+/-122.7 and 255.9+/-121.8 ng h/ml, Cmax values were 54.8+/-29.5 and 57.2+/-29.0 ng/mL, Tmax values were 4.6+/-1.6 h and 4.3+/-1.45 h, and t1/2 ranged between 1.1 to 10.5 h (4.5+/-2.9) and 0.6 to 9.4 h (3.5+/-2.5) for the two brands. CONCLUSIONS: Cmax values for enalapril are about 10 times those published in the literature and the rate and extent of absorption of the two brands of enalapril and their deesterification to enalaprilat following the administration of either brand were bioequivalent. Secondly, enalaprilat concentrations at 12-24 h following a single oral dose of enalapril in healthy volunteers were lower than those reported in the literature. The values reported here correlated with the return of blood pressure to predose level. Thirdly, enzyme immunoassays for enalapril and enalaprilat are better than ACE inhibition assays and can be used in bioequivalence assessment of enalapril and enalaprilat and for therapeutic drug monitoring in a clinical laboratory setting.

Absorption↗
PubMed1988

Effect of intravenous enalaprilat in moderate and severe systemic hypertension.

The antihypertensive effect and tolerability of enalaprilat, an intravenously administered angiotensin converting enzyme inhibitor, was studied in 65 patients with moderate or severe hypertension. In this randomized, double-blind study, enalaprilat was compared with placebo in 42 (22 enalaprilat, 20 placebo) moderate hypertensive (diastolic blood pressure [BP] 100 to 114 mm Hg) patients. It was compared with furosemide in 23 (12 enalaprilat, 11 furosemide) severe hypertensive (diastolic BP 115 to 130 mm Hg) patients. Enalaprilat (1.25 or 5.0 mg), placebo (5% dextrose) or furosemide (40 or 80 mg) was given every 6 hours intravenously up to 48 hours. In the moderate hypertension stratum, the mean supine diastolic BP was significantly (p less than or equal to 0.01) reduced from baseline at all timepoints in the enalaprilat group. These diastolic BP reductions were significantly (p less than or equal to 0.01) greater in the enalaprilat group than the placebo at 1 to 24 hours (-12 vs -4 mm Hg), with 59% of the patients responding to enalaprilat compared with 30% of the patients responding to placebo. An even greater reduction (p less than or equal to 0.01) was seen at 25 to 48 hours (-14 vs -7 mm Hg, with 73% enalaprilat vs 58% placebo responders). Significant (p less than or equal to 0.01) reductions in mean, supine systolic BP were also seen at 1 to 24 hours (-22 vs -2 mm Hg) and 25 to 48 hours (-24 vs -8 mm Hg) during the 48 hours of the double-blind treatment phase in the enalaprilat group compared with placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

Antihypertensive Agents↗
PubMed1990

A physiological model for renal drug metabolism: enalapril esterolysis to enalaprilat in the isolated perfused rat kidney.

A physiologically based kidney model was developed to describe the metabolism of enalapril and explain the observed discrepancies between generated and preformed enalaprilat (metabolite) elimination in the constant flow single-pass and recirculating isolated perfused rat kidney preparations (IPKs) as a result of the differing points of origin of the metabolite within the kidney, subsequent to the simultaneous delivery of 14C-enalapril and 3H-enalaprilat. The model incorporated clearances for diffusion/transport of drug and metabolite across the basolateral and luminal membranes of the renal cells, an intrinsic clearance for renal drug metabolism, in addition to physiological variables such as perfusate flow rate, glomerular filtration rate, and urine flow rate. Nonlinear curve fitting of single-pass and recirculating data was performed to estimate the rate-limiting step in the renal elimination of enalaprilat. Through fitting and simulation procedures, we were able to predict metabolic and excretory events for enalapril (renal extraction ratio approximately equal to 0.25-0.3; fractional excretion, FE, was less than unity) and the relatively constant pattern of urinary excretion of preformed enalaprilat (extraction ratio approximately equal to 0.07; FE approximately equal to 1). The extraction ratio of the intrarenally formed enalaprilat in single-pass IPK was about twofold that for the preformed metabolite, whereas the FEs of generated enalaprilat in recirculating IPKs were greater than 1, and tended to increase, then decrease with perfusion time. These observations were explained by the optimized parameters which indicated that efflux from cell to lumen was rate-controlling in the excretion of enalaprilat, and another small transport barrier also existed at the basolateral membrane; the lower extraction ratio of preformed enalaprilat was due to its poor transmembrane clearance at the basolateral membrane. The variable FEs for generated enalaprilat vs. the relatively constant FE for preformed metabolite in the recirculating IPK was explained by the changing contributions of both circulating and intrarenal metabolite to metabolite excretion.

Animals↗
PubMed2000

Intracoronary enalaprilat improves metabolic coronary vasodilation in patients with idiopathic dilated cardiomyopathy.

Coronary flow reserve is reduced in patients with idiopathic dilated cardiomyopathy (DCM). We examined acute effects of intracoronary enalaprilat on metabolic coronary vasodilation during pacing tachycardia in patients. Coronary blood flow (Doppler guidewire) and diameter (quantitative angiography) were measured in seven patients with DCM and seven control subjects. In the DCM group, tachypacing increased coronary blood flow by 37 +/- 22% from the baseline before enalaprilat and by 65 +/- 22% (p < 0.01 vs. before treatment) after enalaprilat (0.5 microg/kg/min for 5 min, i.c.) at comparable double product. Pacing-induced dilation of the epicardial coronary artery also was greater after enalaprilat (p < 0.05). Effects of enalaprilat on coronary blood flow and diameter during pacing tachycardia were abolished by pretreatment with intracoronary administration of the nitric oxide (NO) synthesis inhibitor, N(G)-monomethyl-L-arginine. These beneficial effects of enalaprilat on large and small coronary vasodilation were not observed in control patients. Thus, intracoronary enalaprilat acutely augmented dilator responses of the large and small coronary arteries to pacing tachycardia in patients with DCM, and NO appeared to play an important role in mediating the effects of enalaprilat. These favorable effects of enalaprilat on the coronary circulation may be of clinical significance in patients with heart failure due to nonischemic DCM. Further long-term studies of the effects of angiotensin-converting enzyme inhibition on coronary vasodilation will be needed in this population.

Aged↗
PubMed2002

Enalaprilat improves systemic cardiovascular parameters and mesenteric blood flow during hypotensive resuscitation from hemorrhagic shock in dogs.

Resuscitative interventions that improve mesenteric perfusion without causing instability in systemic arterial pressures may be helpful for improving trauma patient outcomes. Blocking angiotensin II formation with enalaprilat may be such an intervention. Two questions were addressed in this two-part study investigating resuscitation from hemorrhagic shock in dogs: Can systemic arterial pressures be maintained while administering a constant rate infusion of enalaprilat during resuscitation, and can enalaprilat improve cardiovascular status during resuscitation? Animals were hemorrhaged to a mean arterial pressure (MAP) of 40 to 45 mmHg for 30 min and then 30 to 35 mmHg for 30 min. Group I (n = 5) was resuscitated to a MAP 60 to 65 mmHg with enalaprilat (0.02 mg/kg/h). Group II was resuscitated to a MAP 40 to 45 mmHg with (n = 5) or without (n = 5) enalaprilat. Resuscitation in both groups consisted of intermittent intravenous lactated Ringer's solution (60 mL/kg/h) to reach and maintain the target MAPs. Systemic arterial pressures were unaffected by enalaprilat during resuscitation in Group I, allowing us to proceed to the second study. During severely hypotensive resuscitation (Group II), systemic arterial pressures were also stable and enalaprilat administration was associated with increases (P < or = 0.02) in cardiac index (+1.2 L/min/m2), stroke volume index (SVI) (+14.5 mL/m2), superior mesenteric artery flow (+80 mL/min), stroke work (+561 mmHg/mL/m2), and left ventricular power output (+55.7 mmHg/L/min/m2). Corresponding increases were not observed in controls. We conclude that administration of a constant rate infusion of enalaprilat during resuscitation can be accomplished without causing a hypotensive crisis. Since enalaprilat significantly improved cardiovascular status including mesenteric perfusion even during intentional hypotension, it has potential value for improving the treatment of trauma patients.

Animals↗
PubMed1994

Isolated circulatory response to intravenous administration of the ACE inhibitor enalaprilat.

The isolated vascular effects of intravenous administration of the angiotensin converting enzyme (ACE) inhibitor enalaprilat were investigated. Thirty male patients undergoing cardiopulmonary bypass (CPB) were studied. According to a randomized sequence, 0.04 mg kg-1 enalaprilat (low-dose, n = 10), 0.08 mg kg-1 (high-dose, n = 10) enalaprilat or saline solution as placebo (control group, n = 10) was given as an i.v. bolus during CPB. Changes in mean arterial pressure (MAP) and venous reservoir (RV) of the extracorporeal circulation were studied as indices of arterial resistance and venous capacitance. Mean arterial blood pressure (MAP) and peripheral vascular resistance (SVR) were significantly more reduced in the high-dose enalaprilat group (MAP: -36 mm Hg after 9 min; SVR: -836 dyn s cm-5) than in the low-dose group (MAP: -13 mm Hg after 10 min). Volume of the reservoir (RV) decreased in both enalaprilat treated groups indicating additional (dose-dependent) venous pooling effects of the substance (low-dose: -300 ml; high-dose: -520 ml; control group: -100 ml). Skin capillary blood flow measured by laser Doppler flowmetry (LDF) increased after injection of 0.04 mg kg-1 enalaprilat, whereas it decreased significantly when MAP fell markedly in patients treated with high-dose enalaprilat. I.v. enalaprilat had dose-dependent vasodilating properties in the arterial and venous vessel system indicating reduction in pre- and afterload. Microcirculation in both enalaprilat treated groups improved as long as reduction in blood pressure was not limited.

Blood Pressure↗
PubMedDate not supplied

Presence of a diffusional barrier on metabolite kinetics: enalaprilat as a generated versus preformed metabolite.

Studies in the once-through perfused rat liver with the simultaneous delivery of 14 C-enalapril and its polar diacid metabolite, 3H-enalaprilat, revealed different extents of elimination (exclusively by biliary excretion) for the generated (14C-enalaprilat) and preformed (3H-enalaprilat) metabolite (18 and 5% dose) [Pang, Cherry, Terrell, and Ulm: Drug Metab. Dispos. 12, 309-313 (1984)]. The present re-examination of data provided an explanation for these discrepant observations: enalaprilat, being a polar dicarboxylic acid, encounters more of a diffusional barrier than its precursor, enalapril, an ethyl ester of enalaprilat. Programs written in Fortran 77 on mass balance relationships were employed to simulate data upon varying the diffusional clearances for drug (CLd) and metabolite [CLd(mi)] from 1 to 5000 ml/min. The metabolic and biliary intrinsic clearances for drug and metabolite were found by trial and error such that the combinations of all clearance parameters yielded data similar to enalaprilat, and 3H-enalaprilat. Our finding indicated that the diffusional clearance for enalaprilat was low (2 ml/min) compared to that of enalapril (75 ml/min). The presence of a diffusional barrier for enalaprilat retards entry of the preformed metabolite into hepatocytes but prevents efflux of the intracellularly formed generated metabolite into sinusoidal blood, thereby enhancing generated metabolite elimination.

Animals↗
PubMed1986

Enalaprilat: an intravenous substitute for oral enalapril therapy. Humoral and pharmacokinetic effects.

Thirteen subjects with essential hypertension controlled on oral enalapril (20 mg/day) therapy were entered into a protocol to assess serially 24-hour blood pressure, the renin-angiotensin-aldosterone system, angiotensin-converting enzyme activity, and plasma and urine enalaprilat drug levels, following both chronic oral administration of enalapril and its replacement with intravenous enalaprilat. Results indicate that systolic and diastolic blood pressures remain well controlled following cessation of oral enalapril and replacement with intravenous enalaprilat. Enalaprilat drug levels, following oral enalapril and intravenous enalaprilat, remained above the therapeutic levels required for angiotensin-converting enzyme inhibition. However, therapeutic enalaprilat levels can probably be achieved with one fourth of the total cumulative dose of enalapril, administered as enalaprilat at 6-hour intervals. Intravenous enalaprilat stimulated plasma renin activity and decreased immunoreactive plasma angiotensin II and plasma aldosterone concentrations. However, immunoreactive plasma angiotensin II concentrations were not suppressed below pretreatment values, suggesting that chronic enalapril/acute enalaprilat therapy controls blood pressure through a nonangiotensin-mediated antihypertension mechanism.

Administration, Oral↗
PubMed1999

[Sublingual nitroglycerin or intravenous enalaprilat in preclinical treatment of hypertensive patients with pulmonary edema].

In a prospectively designed randomized study, we compared the efficacy of sublingual nitroglycerine and intravenous enalaprilat in the out-of-hospital treatment of 46 hypertensive patients with pulmonary edema (defined as rales over both lungs and systolic blood pressure > 200 mm Hg and diastolic blood pressure > 100 mg). The out-of-hospital treatment consists of oxygen (6 Ll/min) via a face mask, furosemide 80 mg i.v., opioids 10 mg s.c., and either sublingual nitroglycerine (n = 23; initial dose: 0.8 mg; repetitive application of 0.8 mg every 10 min until a cumulative dose of 3.2 mg) or intravenous enalaprilat (initial dose: 2.5 mg; repetitive application of 2.5 mg every 30 min until a cumulative dose of 10 mg). The aim of the antihypertensive treatment was a reduction of systolic blood pressure below 160 mm Hg and diastolic blood pressure below 90 mm Hg until admission to the emergency department. In the emergency room, an arterial and venous blood sample was taken to determine the respiratory (pO2, pCO2) and metabolic status (pH value; base-excess; serum lactate) of the patient. Successful antihypertensive treatment was observed in 13/23 (57%) patients of the enalaprilat group and 15/23 (65%) patients of the nitroglycerine group (p = 0.54). Systolic and diastolic blood pressure on admission were similar in both treatment groups (systolic RR: enalaprilat: 179 [31] mm Hg; nitroglycerine: 184 [38] mm Hg; p = 0.59; diastolic RR: enalaprilat: 96 [14] mm Hg; nitroglycerine: 101 [14] mm Hg; p = 0.12). No significant differences were observed between the enalaprilat and the nitroglycerine groups concerning respiratory and metabolic parameters on admission (pO2: 67 [15] vs. 64 [17] mm Hg; p = 0.50; pCO2: 46 [9] vs. 47 [13]; p = 0.75; pH value: 7.27 [0.12] vs. 7.27 [0.09]; p = 0.98; BE: -4.2 [3.7] vs. -5.7 [4.1]; p = 0.23; lactate: 4.2 [3.3] vs. 4.2 [2.7]; p = 0.98). Intravenous enalaprilat did not exhibit any advantage compared to nitroglycerine in terms of blood pressure reduction or respiratory and metabolic parameters on admission to the emergency room. We conclude that enalaprilat is no substitute for nitroglycerine in the out-of-hospital treatment of hypertensive patients with pulmonary edema.

Administration, Sublingual↗
PubMed1996

Enalaprilat augments arterial and cardiopulmonary baroreflex control of sympathetic nerve activity in patients with heart failure.

OBJECTIVES: This study sought to determine the effects of enalaprilat on reflex control of sympathetic nerve activity. BACKGROUND: Angiotensin-converting enzyme inhibitors decrease mortality in patients with congestive heart failure. Their efficacy appears to be related importantly to antiadrenergic effects, the mechanism for which has not been determined. Because baroreflexes tonically inhibit sympathetic outflow, and baroreflexes are blunted in heart failure, we hypothesized that these agents reduce sympathetic activity by augmenting baroreflexes. METHODS: We assessed baroreflex control of sympathetic nerve activity and heart rate in patients with congestive heart failure and in control subjects before and after enalaprilat (0.02 mg/kg body weight intravenously). Arterial baroreflexes were perturbed by bolus administration of sodium nitroprusside and phenylephrine. Cardiopulmonary baroreflexes were perturbed by lower body negative pressure and head-down tilt. Muscle sympathetic nerve activity was recorded by microneurography. RESULTS: Enalaprilat decreased systolic blood pressure in patients with heart failure and control subjects. Sympathetic nerve activity increased in control subjects but decreased in patients with heart failure after enalaprilat despite reductions in central venous pressure in this group. Baroreflex control of sympathetic nerve activity was unchanged by enalaprilat in control subjects. In patients with heart failure, both arterial and cardiopulmonary baroreflex control of sympathetic nerve activity was enhanced by enalaprilat. Baroreflex control of heart rate was unchanged by enalaprilat in either group. CONCLUSIONS: Enalaprilat augments both arterial and cardiopulmonary baroreflex control of sympathetic activity in heart failure. These augmented inhibitory influences are associated with a reduction in sympathetic outflow and may contribute to the beneficial effects of angiotensin-converting enzyme inhibitors in heart failure.

Adult↗
PubMed1992

Renal handling of enalaprilat.

Most converting enzyme inhibitors share a predominantly renal dual elimination pathway consisting of glomerular filtration and tubular secretion. Since enalaprilat has two functional acidic groups, it is likely that it may be secreted via the proximal tubule organic acid system and, thus, its clearances would exceed that of glomerular filtration rate markers. We therefore examined the renal clearance of enalaprilat in normal volunteers and compared it with simultaneously measured inulin and creatinine clearances to explore the contribution of tubular secretion to the renal elimination of the drug. Twelve healthy male subjects with an age range of 24 to 58 years (mean +/- SE, 33.1 +/- 2.8) were studied. They had representative height (178.6 +/- 1.99 cm) and weight (73.3 +/- 2.1 kg) and had normal renal function as judged by blood urea nitrogen (BUN) (6 +/- 0.3 mmol/L [17 +/- 0.8 mg/dL]), plasma creatinine (88 +/- 3 mumol/L [1.0 +/- 0.03 mg/dL]), and creatinine clearance determined by a prestudy 24-hour urine collection (123.2 +/- 6.2 mL/min). Results are as follows: mean creatinine clearance, 2.12 mL/s (127 mL/min); mean inulin clearance, 119.1 ml/min mean creatinine clearance/inulin clearance, 1.07 mean enalaprilat protein binding, 37.9% unbound enalaprilat clearance, 222.4 ml/min; and the mean fractional enalaprilat clearances were: enalaprilat clearance/creatinine clearance, 1.72 (P less than 0.05, difference from 1.0); enalaprilat clearance/inulin clearance, 1.85, (P less than 0.05, difference from 1.0). Our results demonstrate that the clearance of free enalaprilat exceeds that of inulin and creatinine, suggesting that elimination of the drug proceeds through two complementary pathways, namely glomerular filtration and tubular secretion.

Adult↗
PubMed2002

Investigation of polymeric nanoparticles as carriers of enalaprilat for oral administration.

Enalaprilat is a typical angiotensin-converting enzyme inhibitor and is very poorly absorbed from the gastrointestinal tract. The aim of this study was to design and characterize poly-(lactide-co-glycolide) (PLGA) and polymethylmethacrylate (PMMA) nanoparticles containing enalaprilat and to evaluate the potential of these colloidal carriers for the transport of drugs through the intestinal mucosa. Nanoparticle dispersions were prepared by the emulsification-diffusion method and characterized according to particle size, zeta potential, entrapment efficiency and physical stability. Effective permeabilities through rat jejunum of enalaprilat in solution and in enalaprilat-loaded nanoparticles were compared using side-by-side diffusion chambers. The solubility of enalaprilat is very low in many acceptable organic solvents, but in benzyl alcohol is sufficient to enable the production of nanoparticles by the emulsification-diffusion process. The diameters of drug-loaded PMMA and PLGA nanoparticles were 297 and 204 nm, respectively. The concentration of the stabilizer polyvinyl alcohol (PVA) in dispersion has an influence on particle size but not on drug entrapment. The type of polymer has a decisive influence on drug content--7 and 13% for PMMA and PLGA nanoparticles, respectively. In vitro release studies show a biphasic release of enalaprilat from nanoparticle dispersions-fast in the first step and very slow in the second. The apparent permeability coefficient across rat jejunum of enalaprilat entrapped in PLGA nanoparticles is not significantly improved compared with enalaprilat in solution.

Administration, Oral↗