THE PHYSIOLOGICAL DISPOSITION AND METABOLISM OF ENALAPRIL MALEATE IN LABORATORY-ANIMALS

Abstract

N-[1-(S)-carboxy-3-phenylpropyl]-L-alanyl-L-proline (MK-422), is a potent angiotensin I-converting enzyme (ACE) inhibitor, but as a diacid is poorly absorbed in laboratory animals. Enalapril maleate, the monoethyl ester of MK-422, proved to be significantly better absorbed in both rats and dogs. Peak levels of radioactivity in plasma occurred in 30 min in rats and 2 h in dogs after a single dose of 14C-enalapril maleate (1 mg/kg, per os). Rats excreted 26% of the dose in the urine and 72% in the feces in 72 h, dogs excreted 40% of the dose in the urine and 36% in the feces. After the i.v. dose, the presence of radioactivity in the feces of both species suggested that some biliary excretion had occurred. Absorption was estimated to be 34% in the rat and 61% in the dog. The major metabolite of enalapril maleate in dogs, accounting for 86% of the urine radioactivity, was identified as MK-422 by GC/MS [gas chromatography-mass spectroscopy]. A procedure was developed for the quantitation of MK-422 and enalapril in plasma and urine by their inhibition of purified ACE. The assays showed that enalapril was absorbed intact in dogs and converted to MK-422 after absorption. [The data may be useful in establishing suitable protocols for its therapeutic use for treating hypertension in man.].