TIGHT-BINDING OF RAMIPRILAT TO ACE - CONSEQUENCES FOR PHARMACOKINETICAND PHARMACODYNAMIC MEASUREMENTS

The pharmacokinetics of angiotensin converting enzyme (ACE) inhibitors are often difficult to characterize using standard tools. Most of the problems arise from the tight binding of ACE inhibitors to ACE. The p resent paper discusses how tight binding of ramiprilat to ACE affects the pharmacokinetic characteristics and in vitro measurement of ACE in hibition. Data from a randomized crossover study in healthy volunteers given 2 different dosage forms with 5 mg ramipril serve to compare th e theoretically deduced predictions with actual measurements. The data confirm that elimination is concentration-dependent and that therefor e the pharmacokinetics are non-linear, Renal clearance increases with concentration, With respect to pharmacodynamics, free ramiprilat deple tion due to tight binding is the reason for the steep nature of concen tration-effect curves often observed for ACE inhibition. This type of relationship, however, cannot be described by the classical E(max) mod el nor by the sigmoid E(max) model. The model of tight binding present ed shows that the concentration-effect curve becomes steeper the large r the concentration of ACE and the greater the affinity of the inhibit or to the target molecule. With the classical E(max) model the concent ration can be doubled about 3 times to increase the measurable effect from 10 to 50% maximum effect, and because the relationship is symmetr ic at the EC(50%) point of inflection, the concentration can be double d another 3 times to increase the effect from 50 to 90%. With the tigh t-binding concentration-effect relationship, doubling the concentratio n about 3 times may also increase the effect from 10 to 50% of the max imum effect, a further doubling of the dose, however, causes a steep i ncrease of the effect from 50 to nearly 100%. This tight-binding conce ntration-effect relationship may also be present in other classes of d rugs.