Moexipril shows a long duration of action related to an extended pharmacokinetic half-life and prolonged ACE inhibition.
OBJECTIVE
To characterize the lipophilic ACE inhibitor moexipril and its active metabolite moexiprilat regarding the duration of action, the susceptibility of the pharmacokinetics and pharmacodynamics to food intake and the concentration-dependent effect.


METHODS
Three independent, open, randomized studies were performed in healthy subjects using crossover or parallel-group designs. In the first study, pharmacokinetics (AUC, Cmax, tmax, t 1/2) and ACE inhibition (up to 72 h) were investigated following single oral doses of 15 mg moexipril administered in the fasting and postprandial state (n = 24). The individual ACE inhibition data and plasma concentration data were fitted to an Emax model. In the second study, carried out in 52 volunteers, the pharmacokinetics were followed over 36 h following administration of 2 single oral doses of 15 mg moexipril. In the third study, the pharmacokinetics after multiple dosing of 15 mg moexipril once daily for 5 days were investigated in 12 young and 12 elderly subjects.


RESULTS
Moexiprilat tmax was 1.5-2 h with only minor differences between single and multiple dosing. Compared to fasting, the postprandial moexiprilat Cmax and AUC (ratio fed/fasted 58.0%; 90% CI 52.2-64.5%) were distinctly reduced (ANOVA p = 0.0001). Moexiprilat showed a biphasic elimination phase with an average t 1/2 of 29-30 h. In contrast to the alpha-phase, the plasma concentrations during the terminal elimination phase were not affected by food. A relationship between ACE inhibition and plasma concentration was not observed. The average ACE inhibition over 72 h was 71 % in the fasting state and 74% in the postprandial state. ACE inhibition increased to about 80% after 24 h and decreased to about 60% at 72 h. The S-shaped concentration-effect curve indicated that a moexiprilat level of 1.3 ng/ml was sufficient to produce 50% inhibition of ACE. With repeated dosing there were no signs of drug accumulation and day-to-day drug levels were relatively constant. The trough concentrations at 24 h did not fall below the limit of 1-2 ng/ml, i.e. a 50% ACE inhibition.


CONCLUSIONS
Moexiprilat showed an extended duration of action owing to a long terminal pharmacokinetic half-life and produced a persistent ACE inhibition. Although the pharmacokinetics were partly influenced by food intake, ACE inhibition was not affected. This might be explained by a second compartment directly related to the ACE which is less prone to food effects and the reaching of a ceiling in the sigmoidal concentration-effect curve even with the lower Cmax concentrations associated with the postprandial state.
Cawello
W
W
Schwarz Pharma AG, Monheim, Germany. Willi.Cawello@SchwarzPharma.com
Boekens
H
H
Waitzinger
J
J
Miller
U
U
D000328:Adult; D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D018565:Food-Drug Interactions; D006207:Half-Life; D006801:Humans; D007546:Isoquinolines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D007703:Peptidyl-Dipeptidase A / Q000097:blood; D044005:Tetrahydroisoquinolines
D000806:Angiotensin-Converting Enzyme Inhibitors; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D007703:Peptidyl-Dipeptidase A; C059506:moexiprilat; C058302:moexipril