enalaprilat-anhydrous and Liver-Cirrhosis

The possibility of an impaired hepatic de-esterification of enalapril to enalaprilat due to hepatic dysfunction was assessed in seven patients with compensated liver cirrhosis and 10 normal control subjects. The peak serum concentration and time to the peak serum concentration of enalaprilat, as well as the suppression of serum angiotensin converting enzyme activity, following a single oral dose of enalapril maleate (10 mg) were not different in the two groups. The elimination half-life of enalaprilat was related to renal function. The results suggest that hepatic biotransformation of the drug may not be disturbed in a clinically significant manner in patients with moderate hepatic dysfunction due to compensated liver cirrhosis.

Topics: Adult; Enalapril; Enalaprilat; Half-Life; Humans; Liver Cirrhosis; Male; Middle Aged; Peptidyl-Dipeptidase A; Radioimmunoassay

The pharmacokinetics and pharmacodynamics (blood pressure, heart rate, serum angiotensin-converting enzyme, and plasma renin activity) of enalapril and enalaprilat were studied after oral administration of enalapril maleate (10 mg) to seven biopsy-proven cirrhotic patients and to seven healthy subjects. The mean Cmax, AUC, and urinary excretion of enalapril and enalaprilat were greater and less (p less than 0.01), respectively, and mean oral clearance of enalapril was less (p less than 0.01) in the cirrhotic group than in the healthy group. However, there was no significant difference in the mean total drug (enalapril plus enalaprilat) excretion between the two groups. Blood pressure fell (p less than 0.05) only at 3 or 4 hours postdose, with no change in heart rate in the two groups. Serum angiotensin-convering enzyme (ACE) decreased (p less than 0.001) and plasma renin activity (PRA) increased (p less than 0.05) in the two groups. The magnitude of the percentage of inhibition of ACE activity was comparable between the two groups. Serum enalaprilat concentration correlated (p less than 0.001) with the percentage of inhibition of ACE activity. The results suggest that the bioactivation of enalapril to enalaprilat is considerably impaired in patients with cirrhosis but that the pharmacodynamic effects do not appear to be blunted in those patients. The mechanism and clinical implications remained unclear.

Topics: Administration, Oral; Aged; Blood Pressure; Enalapril; Enalaprilat; Heart Rate; Humans; Liver Cirrhosis; Male; Middle Aged; Peptidyl-Dipeptidase A; Renin