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.
Conclusion: 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.