Enalapril Clinical Pharmacokinetics and Pharmacokinetic-Pharmacodynamic Relationships

Abstract

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)

Endogenous production of angiotensin II modulates rat proximal tubule transport.

“…Next, to examine whether production of endogenous angiotensin II affects fluid reabsorption, 10 Ϫ 4 M enalaprilat was added to the perfusion solution. Enalaprilat blocks angiotensin converting enzyme and prevents the formation of angiotensin II from its precursor, angiotensin I (19). As seen in Fig.…”

“…We also examined the effect of 10 Ϫ 4 M enalaprilat on the rate of proximal tubule volume absorption. Enalaprilat (Merck & Co., West Point, PA), an angiotensin converting enzyme inhibitor, prevents the production of angiotensin II from angiotensin I (19). Similarly, tubules were randomly perfused with either enalaprilat or control to avoid bias.…”

ABPM Comparison of the Anti-Hypertensive Profiles of Telmisartan and Enalapril in Patients with Mild-to-Moderate Essential Hypertension

“…The prolonged phase does not contribute to drug accumulation on repeated administration, but is thought to be of pharmacological significance in mediating drug effects, such as blood pressure control. 22 Telmisartan also displays biphasic elimination, with a terminal elimination half-life that varies in different studies, but is usually quoted as being about 24 h. 23 Thirdly, ABPM has shown that enalapril has 24-h anti-hypertensive efficacy and that it is more effective than placebo or nitrendipine in lowering blood pressure during the night-time -a time when a shorter acting agent would confer less blood pressure control. 24,25 The ability of an anti-hypertensive agent to maintain effective 24-h blood pressure control is an important consideration in light of the excess of cardiovascular events that occur during the morning hours.…”

Characterization of the Pharmacokinetic and Pharmacodynamic Properties of the Angiotensin‐Converting Enzyme Inhibitor, Enalapril, in Horses

“…In humans, the t 1/2 of enalapril is about 2 hours, and enalaprilat elimination is biphasic with an initial phase that reflects renal clearance with a t 1/2 of about 4 hours and a protracted phase that reflects saturable binding to tissue and plasma ACE with a t 1/2 of approximately 35 hours. [29][30][31][32] Because of ACE binding, enalaprilat disposition is best described in humans by a physiologically based model. 31,[33][34][35] This model has also been used to describe enalaprilat disposition in dogs.…”

“…[29][30][31][32] Because of ACE binding, enalaprilat disposition is best described in humans by a physiologically based model. 31,[33][34][35] This model has also been used to describe enalaprilat disposition in dogs. 36,37 It is possible that the protracted terminal phase representing binding of enalaprilat to tissue and plasma ACE and prolonged t 1/2 may also exist in the horse, but we were unable to evaluate it as the LOQ of our LC/MS assay (5 ng/mL) was greater than that of the radioimmunoassay (0.4 ng/mL) used in the human studies described earlier.…”