Comparative Pharmacodynamics of Eight Calcium Channel Blocking Agents in Japanese Essential Hypertensive Patients.

Abstract

The relationships between plasma drug concentration and antihypertensive effect of eight calcium channel antagonists (nicardipine, nifedipine, nilvadipine, benidipine, manidipine, barnidipine, nitrendipine and efonidipine) in Japanese essential hypertensive patients were analyzed. Based on the effect compartment model, we could explain the long duration of the pharmacological effect, and there was significant correlation (r = 0.876, p < 0.05) between estimated EC50 values and the dissociation constants (Kd) obtained from in vitro binding studies. We also developed the ion-channel binding model to understand the pharmacodynamics of long acting calcium antagonists. The model was also well fitted to antihypertensive effect data. A significant correlation between the apparent in vivo dissociation constants and in vitro Kd values was observed with a slope of 1.45 (r = 0.913), suggesting that the mechanism of long-lasting antihypertensive effect of newer developed calcium antagonists is due to their high binding affinity at ion-channel sites.

Pharmacokinetic-Pharmacodynamic Modeling of the Antinociceptive Effect of Buprenorphine and Fentanyl in Rats: Role of Receptor Equilibration Kinetics

“…Similar correlations have been reported for calcium channel antagonists using a receptor association/dissociation model (Shimada et al, 1996) and also for A 1 adenosine receptor agonists and GABA A receptor modulators using a different mechanism-based PK/PD model based on receptor theory (Van der Graaf et al, 1999;Visser et al, 2003). Moreover, the ability to estimate an in vivo K D allows a strict quantitative comparison with the antinociceptive effect of other compounds.…”

“…A common feature of these models is that rapid equilibration of the drug-receptor complex is assumed. However, some drugs do not bind rapidly with their pharmacological target, and therefore the time course of drug effect is influenced by the kinetics of the target equilibration (Shimada et al, 1996). In this investigation, a mechanism-based PK/PD model is proposed which contains specific expressions for the kinetics of the drug-receptor interaction in vivo.…”

Diversity of Mechanism-Based Pharmacodynamic Models

“…8 -10). In contrast, an ion-channel binding model has been developed by Shimada et al (1996) on the basis of in vitro binding data of calcium channel antagonists, which demonstrate relatively slow rates of association and dissociation. The pharmacological effect is still assumed to be proportional to the concentration of the drug-receptor complex, and in a direct parallelism to eq.…”

Novel CNS drug discovery and development approach: model-based integration to predict neuro-pharmacokinetics and pharmacodynamics

“…Moreover, for studies with only PK and PD observations but not TO data, a delay between the PK and PD is often be explained by a biophase (or effect compartment) distribution model. However, incorporating drug-target binding into the model might explain the same delay and could be more mechanistic [64]. On the other hand, when solving the shortcomings in knowledge on target site distribution of drugs, the principles of the operational model of agonism (receptor theory) will provide the basis for future developments in drug development by classifying drugs and predicting their mechanism of action in pharmacology [65][66][67][68].…”