Evaluation of pharmacokinetic and pharmacodynamic relationship for oral sustained-release atenolol pellets in rats

Abstract

This study was designed to evaluate the in vitro release, pharmacokinetics (PK), pharmacodynamics (PD) and PK–PD relationships of atenolol sustained-release pellets (AT-SRPs), compared with those of atenolol immediate-release pellets (AT-IRPs). Blood sampling for AT plasma concentration was performed in normal rats and blood pressure-lowering effects were recorded continuously in hypertensive rats (HRs) before and at 1, 4, 8, 12, 16 and 24 h after drug administration. The parameters were calculated using DAS1.0 program and WinNonlin software. The release profile of SRPs was steadier and more sustained than that of IRPs. The mean C max and area under concentration–time curve from 0 to 24 h after administration (AUC 0–24 h ) of SRPs were significantly lower than that of IRPs ( p < 0.05), while area under concentration–time curve from 0 to infinity (AUC 0–∞) was almost equivalent between the two formulations. The mean half life time ( t 1/2) of AT-SRPs was almost 2 times longer compared to that of AT-IRPs. The SRPs approximately achieved half of peak drug effect ( E max) of IRPs, while there were no significant differences in the area under effect–time curve from 0 to 24 h after administration (AUEC 0–24 h ) and the area under effect–time curve from 0 to infinity (AUEC 0−∞). The value of the rate constant of equilibration between plasma and the effect-site ( k e0) for SRPs was about 4 times higher than IRPs. The effect–concentration–time course for AT-SRPs was represented by the clockwise hysteresis loop, while the counter-clockwise hysteresis loop well showed that for AT-IRPs. The more favorable characteristics of SRPs would make it more appropriate as a potential dosage form for the treatment of hypertension.