Chemical formula: C₂₀H₂₈N₂O₅ Molecular mass: 376.447 g/mol PubChem compound: 5388962
After oral administration in adults, enalapril is hydrolysed via hepatic CES 1 to the active metabolite enalaprilat, which acts as an ACE inhibitor. ACE is a peptidyl dipeptidase which catalyses the conversion of angiotensin I to the vasoconstrictor substance angiotensin II and hence inhibition of ACE results in decreased plasma angiotensin II. This also leads to increased plasma renin activity (due to removal of negative feedback of renin release), and decreased aldosterone secretion. The mechanism of action of enalapril is therefore primarily via the suppression of the RAAS. However, ACE is identical to kininase II, and so enalapril may also exert its effects by blocking the degradation of bradykinin, a potent vasodepressor peptide.
Questions remain regarding the differential effects of ACE inhibition on RAA axis depending on the paediatric age range in question.
Oral enalapril is rapidly absorbed, with peak serum concentrations of enalapril occurring within one hour. Based on urinary recovery, the extent of absorption of enalapril from oral enalapril tablet is approximately 60%. Enalapril is rapidly and extensively hydrolysed to enalaprilat, a potent angiotensin converting enzyme inhibitor.
The absorption of enalapril orodispersible tablets is not expected to be affected by food.
As described in the adult population, over the range of concentrations, which are therapeutically relevant, enalaprilat binding to human plasma proteins does not exceed 60%. In adults, the apparent volume of distribution (V/F) of enalapril from enalapril was 93.15 L (SD 33.23 L).
Except for conversion to enalaprilat, there is no evidence for significant metabolism of enalapril.
Excretion of enalaprilat is primarily renal. In adults, after a single oral dose of enalapril (10 mg), 18% of the administered dose was found in urine and 6% in faeces as unchanged enalapril compared with 43% of enalaprilat in urine and 27% in faeces. Elimination kinetics of enalaprilat is biphasic, with an initial phase reflecting renal filtration (elimination half-life 2 to 6 hours) and a subsequent prolonged phase (terminal elimination half-life 36 hours) which is assumed to represent drug equilibration from ACE enzyme binding sites.
Steady state concentrations of enalaprilat are achieved after 3 or 4 doses of enalapril. The principal components in urine are enalaprilat, accounting for about 40% of the dose, and intact enalapril (about 20%). The elimination half-life for enalapril from enalapril in adults was 0.77 h (SD 0.11 h) and oral clearance (CL/F) 87.54 l/h (SD 33.45 l/h).
The exposure of enalapril and enalaprilat is increased in patients with renal insufficiency. In patients with mild to moderate renal insufficiency (creatinine clearance 40-60 ml/min) steady state AUC of enalaprilat was approximately two-fold higher than in patients with normal renal function after administration of 5 mg once daily. In severe renal impairment (creatinine clearance ≤30 ml/min), AUC was increased approximately 8-fold. The effective half-life of enalaprilat following multiple doses of enalapril maleate is prolonged at this level of renal insufficiency and time to steady state is delayed. Enalaprilat may be removed from the general circulation by haemodialysis. The dialysis clearance is 62 ml/min.
After a single 20 mg oral dose in five postpartum women the average peak enalapril milk level was 1.7 µg/l (range 0.54 to 5.9 µg/l) at 4 to 6 hours after the dose. The average peak enalaprilat level was 1.7 µg/l (range 1.2 to 2.3 µg/l); peaks occurred at various times over the 24 hour period. Using the peak milk level data, the estimated maximum intake of an exclusively breastfed infant would be about 0.16% of the maternal weight-adjusted dose.
A woman who had been taking oral enalapril 10 mg daily for 11 months had peak enalapril milk levels of 2 µg/l 4 hours after a dose and peak enalaprilat levels of 0.75 µg/l about 9 hours after the dose. The total amount of enalapril and enalaprilat measured in milk during the 24 hour period was 1.44 µg/l and 0.63 µg/l of milk respectively.
Enalaprilat milk levels were undetectable (<0.2 µg/l) 4 hours after a single dose of enalapril 5 mg in one mother and 10 mg in two mothers; enalapril levels were not determined.
In children with DCM, dose and weight normalised maximum plasma concentrations (Cmax) were 203 ng/ml/mg × kg for enalapril and 155 ng/ml/mg × kg for enalaprilat, with high coefficients of variation of 73% for enalapril and 61% for enalaprilat. Maximum plasma concentrations (Tmax) were of 1.7 hours for enalapril and 4.6 hours for enalaprilat, after administration of enalapril orodispersible tablet (ODT). In children with CHD, dose and weight normalised maximum plasma concentrations (Cmax) were 274 ng/ml/mg × kg for enalapril and 178 ng/ml/mg × kg for enalaprilat, with high coefficients of variation of 58% for enalapril and 82% for enalaprilat. Maximum plasma concentrations (Tmax) were of 1.8 hours for enalapril and 6.3 hours for enalaprilat, after administration of enalapril ODT.
Data from clinical studies in children with heart failure receiving enalapril allow comparison of the pharmacokinetic parameters in children with DCM and CHD in patients aged 1 month to under 6 years of age (see table below). In this age group, DCM patients showed a 50% lower exposure (AUC) to enalapril, compared to CHD patients. The metabolism of the active metabolite enalaprilat, however, was the same for both groups. The time to achieve maximal concentrations Tmax of enalapril were similar.
| Enalapril | Enalaprilat | Enalapril | Enalaprilat | Enalapril | Enalaprilat | ||
|---|---|---|---|---|---|---|---|
| n | AUCtau,ss,norm (ng/ml·h/mg·kg) | Cmax,ss,norm (ng/ml/mg·kg) | tmax or tmax,ss (h) | ||||
| DCM 1 month to <6 years | 20 | 428.3 (235.5–1338.2) | 1040.1 (0–4468.2) | 136.4 (44–760.8) | 120.4 (0–516.3) | 1.99 (0.93–4.17) | 5.37 (0–12.02) |
| CHF 1 month to <6 years | 60 | 785.1 | 1166.3 | 261.0 | 142.1 | 1.98 | 6.0 |
| p DCM versus CHD | 0.0025 | 0.4517 | 0.051 | 0.9543 | 0.7632 | 0.0095 | |
The elimination half life (T½) for enalapril from enalapril in children was 1.67 h and for enalaprilat was 21.66 h.
Although no published results are available describing the PK of enalapril in children with renal impairment, since the drug and its active metabolite are predominantly renally excreted, impaired renal function is expected to result in elevated levels of enalapril and enalaprilat. Thus, the dose of enalapril should be adjusted accordingly and renal function monitored.
Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. Reproductive toxicity studies suggest that enalapril has no effects on fertility and reproductive performance in rats and is not teratogenic. In a study in which female rats were dosed prior to mating through gestation, an increased incidence of rat pup deaths occurred during lactation. The compound has been shown to cross the placenta and is secreted in milk. Angiotensin converting enzyme inhibitors, as a class, have been shown to be fetotoxic (causing injury and/or death to the foetus) when given in the second or third trimester.
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