Pharmacokinetics and converting enzyme inhibition after morning and evening administration of oral enalapril to healthy subjects

Weisser, K; Schloos, J.; Lehmann, K; Düsing, Rainer; Vetter, Hans; Mutschler, E.

doi:10.1007/bf00315146

Cited by 23 publications

(12 citation statements)

References 15 publications

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“…Evening administration leads to a significant prolongation of time to Cmax (tmax) for enalapril, with apparently no significant consequences for the disposition of enalaprilat (Weisser et al 1991). …”

Section: Pharmacokinetics -A Conventional Summarymentioning

confidence: 98%

Enalapril Clinical Pharmacokinetics and Pharmacokinetic-Pharmacodynamic Relationships

MacFadyen

Meredith

Elliott

1993

Clinical Pharmacokinetics

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The conventional pharmacokinetic profile of the angiotensin converting enzyme (ACE) inhibitor, enalapril, is a lipid-soluble and relatively inactive prodrug with good oral absorption (60 to 70%), a rapid peak plasma concentration (1 hour) and rapid clearance (undetectable by 4 hours) by de-esterification in the liver to a primary active diacid metabolite, enalaprilat. Peak plasma enalaprilat concentrations occur 2 to 4 hours after oral enalapril administration. Elimination thereafter is biphasic, with an initial phase which reflects renal filtration (elimination half-life 2 to 6 hours) and a subsequent prolonged phase (elimination half-life 36 hours), the latter representing equilibration of drug from tissue distribution sites. The prolonged phase does not contribute to drug accumulation on repeated administration but is thought to be of pharmacological significance in mediating drug effects. Renal impairment [particularly creatinine clearance < 20 ml/min (< 1.2 L/h)] results in significant accumulation of enalaprilat and necessitates dosage reduction. Accumulation is probably the cause of reduced elimination in healthy elderly individuals and in patients with concomitant diabetes, hypertension and heart failure. Conventional pharmacokinetic approaches have recently been extended by more detailed descriptions of the nonlinear binding of enalaprilat to ACE in plasma and tissue sites. As a result of these new approaches, there have been significant improvements in the characterisation of concentration-time profiles for single-dose administration and the translation to steady-state. Such improvements have further importance for the accurate integration of the pharmacokinetic and pharmacodynamic responses to enalapril(at) in a concentration-effect model.(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Pharmacokinetics -A Conventional Summarymentioning

confidence: 98%

Enalapril Clinical Pharmacokinetics and Pharmacokinetic-Pharmacodynamic Relationships

MacFadyen

Meredith

Elliott

1993

Clinical Pharmacokinetics

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“…Serum and urine concentrations of lisinopril were determined by a modified radioimmunoassay (double antibody technique) with a sheep antiserum and a radioiodinated ligand 351 A (a p-hydroxybenzamidine derivative of lisinopril) [14,15]. The limit of detection amounted to 60 pg-m1-1 for plasma and urine.…”

Section: Measurements and Calculationsmentioning

confidence: 99%

Pharmacokinetics and pharmacodynamics of lisinopril in advanced renal failure

Neubeck

Fliser²,

Pritsch³

et al. 1994

Eur J Clin Pharmacol

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To prevent drug accumulation and adverse effects the dose of hydrophilic angiotensin-converting enzyme (ACE) inhibitors, e.g. lisinopril, must be reduced in patients with renal failure. To obtain a rational basis for dose recommendations, we undertook a prospective clinical trial. After 15 days of lisinopril treatment pharmacokinetic and pharmacodynamic parameters were determined in patients with advanced renal failure (n = 8; endogenous creatinine clearance [CLCR]: 18 ml.min-1.1.73 m-2) and in healthy subjects with normal renal function (n = 16; CLCR: 107 ml.min-1.1.73 m-2). The volunteers received 10 mg lisinopril once daily, the daily dose in patients (1.1-2.2 mg) was adjusted to the individual CLCR according to the method of Dettli [13]. After 15 days of lisinopril treatment the mean maximal serum concentration (Cmax) in patients was lower than in volunteers (30.7 vs 40.7 ng.ml-1, while the mean area under the concentration-time curve (AUC0-24 h) was higher (525 vs 473 ng.h-1.ml-1). ACE activity on day 15 was almost completely inhibited in both groups. Plasma renin activity, angiotensin I and angiotensin II levels documented marked inhibition of converting enzyme in volunteers and patients. Furthermore, average mean arterial blood pressure in patients decreased by 5 mmHg and proteinuria from 3.9-2.7 g per 24 h after 15 days of treatment with the reduced dose of lisinopril. Adjustment of the dose of lisinopril prevents significant accumulation of the drug in patients with advanced renal failure during chronic therapy. Mean serum levels did not exceed this in subjects with normal renal function receiving a standard dose.(ABSTRACT TRUNCATED AT 250 WORDS)

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“…Usually, the dose of renally-excreted drugs is reduced aiming for serum concentrations in the same range as in subjects with normal kidney function, in whom 24-hour trough values of enalaprilat have been shown to be below 5 ng/ml in single, as well as chronic dosing. 18,29,30 Fifty-three (90%) of the patients in the present study had concentrations above this level and 19 (32%) had concentrations more than 10 times higher. As seen in Figure 1, marked elevation of enalaprilat concentrations occurs when GFR is below 30 ml/minute.…”

Section: Discussionmentioning

confidence: 50%

High serum enalaprilat in chronic renal failure

Elung-Jensen

Heisterberg

Kamper

et al. 2001

J Renin Angiotensin Aldosterone Syst

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BackgroundMost angiotensin-converting enzyme (ACE) inhibitors and their metabolites are excreted renally and doses should hence be reduced in renal insufficiency. We studied whether the dosage of enalapril in daily clinical practice is associated with drug accumulation of enalaprilat in chronic renal failure. MethodsFifty nine out-patients with plasma creatinine >150 µmol/L and chronic antihypertensive treatment with enalapril were investigated, in a cross-sectional design. ResultsMedian glomerular filtration rate (GFR) was 23 (range 6-60) ml/minute/1.73 m 2 . The daily dose of enalapril was 10 (2.5-20) mg and the trough serum concentration of enalaprilat was 31.8 (<2.5-584.7) ng/ml. Ninety percent of the patients had higher serum concentrations of enalaprilat than has been reported in subjects with normal kidney function, and a marked elevation of serum enalaprilat was observed in patients with GFR <30 ml/minute. All but three patients had serum ACE activity below the reference range. The ACE genotype did not influence the results. Additional pharmacokinetic studies were done in nine patients in whom GFR was 23 (10-42) ml/minute/1.73 m 2 . The median clearance of enalaprilat was 28 (16-68) ml/minute and correlated linearly with GFR (r=0.86, p=0.003). Intra-subject day-to-day variation in trough concentrations was 19.7%.

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Pharmacokinetics and converting enzyme inhibition after morning and evening administration of oral enalapril to healthy subjects

Cited by 23 publications

References 15 publications

Enalapril Clinical Pharmacokinetics and Pharmacokinetic-Pharmacodynamic Relationships

Enalapril Clinical Pharmacokinetics and Pharmacokinetic-Pharmacodynamic Relationships

Pharmacokinetics and pharmacodynamics of lisinopril in advanced renal failure

High serum enalaprilat in chronic renal failure

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