Pharmacokinetics of Enalapril in Congestive Heart Failure

Summary

The pharmacokinetics of the converting enzyme inhibitor enalapril were studied in an open, randomised, balanced crossover design in 12 hospitalised patients with stable, chronic congestive heart failure (CHF). Enalapril maleate is a prodrug requiring in vivo hepatic esterolysis to yield the active diacid inhibitor enalaprilat. CHF results in changes in regional blood flow that may affect the gastrointestinal absorption, hepatic hydrolysis and renal excretion of enalapril and enalaprilat. In order to evaluate the pharmacokinetics of enalapril in CHF, the following treatments were given: enalapril 10mg orally, enalapril 5mg intravenously and enalaprilat 5mg intravenously. Each dose was followed by a 72-hour period with frequent blood sampling and fractionated urine collection for the radioimmunoassay of both enalapril and enalaprilat. Mean absorption for the oral dose was 69%, hydrolysis 55%, bioavailability 38%, urinary recovery 77% and estimated first-pass effect 10%. The results were compared with available data in normal subjects. After oral administration of 10mg enalapril, the extent of absorption, the degree of hydrolysis and the bioavailability in CHF patients appear to be similar to those in normal subjects, with differences less than 10%. The rates of absorption and hydrolysis appear to be slightly slower in CHF. The serum concentrations of enalaprilat were consistently greater in CHF, and maximal concentrations were reached at 6 hours in CHF compared with 4 hours in normal subjects. The maximal hypotensive responses were similar for all three treatments, although the onset of action was rapid following intravenous enalaprilat. It is concluded that the presence of CHF does not appreciably alter the pharmacokinetic behaviour of enalapril. The observed differences may be associated with age as well as the disease state.