ANALYSIS OF PHARMACOKINETIC-DYNAMIC INTERRELATIONS WITH SPECIAL REFERENCE TO APPLICATIONS IN CARDIOVASCULAR CLINICAL-PHARMACOLOGY

The relationship between a (detectable) cardiovascular response and pl asma concentrations is affected by 1. the temporal delay of the equili brium between sampling site and effector site(s), 2. the intrinsic rel ationship between the primary effect(s) and concentration at the effec tor site(s) and 3. inter-pharmacodynamic processes that link the prima ry effects to a net response and that might attenuate or amplify the p rimary effects. Confounding factors (active metabolites, time-variant protein-binding, enantiospecific pharmacological behavior, physiologic al counter-regulation, etc.) might confuse the issue even more. Models that address kinetic-dynamic interrelations are usually confined to t he first two processes listed above and hardly account for the third f actor (and often are inadequate if more than one confounding factor is involved). They yield model-driven assimilative solutions that are ch aracterized by a high level of indetermination. The ''fit'' of the exp erimental data with an analytical model (in itself usually quite appea ling by its mathematical elegance and inductive creativity) should not be mistaken as a ''match'' between the model and physio-pharmacologic al ''reality''. In consequence, these models are cognitive constructio ns that provide important insight in the complexity of these physio-ph armacological processes without necessarily solving it. Their actual ' 'proof'' and ultimate value thus lies in their practical applicability (i.e. their effective instrumental use) to predict, correct and optim ize (pharmacotherapeutic) response. Unfortunately most models have fai led to be successfully tested in this regard.