Enalapril Clinical Pharmacokinetics and Pharmacokinetic-Pharmacodynamic Relationships

Summary

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. This model is able to characterise the concentration-effect relationship in individual recipients of the drug and predict the antihypertensive responses to dosage alterations.

Therapeutic use of enalapril has recently expanded to include heart failure. In this condition, responses to enalapril may be mediated by different effector systems in different organs and may occur at different concentration ranges to those observed during treatment of hypertension. However, similar concentration-effect analyses are still relevant. After almost 15 years of clinical use, the therapeutic applicability of enalapril continues to expand and detailed pharmacokinetic description of the agent remains an integral component of this expansion.