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

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 Cmax and area under concentration–time curve from 0 to 24 h after administration (AUC0–24 h) of SRPs were significantly lower than that of IRPs (p < 0.05), while area under concentration–time curve from 0 to infinity (AUC0–∞) was almost equivalent between the two formulations. The mean half life time (t1/2) of AT-SRPs was almost 2 times longer compared to that of AT-IRPs. The SRPs approximately achieved half of peak drug effect (Emax) of IRPs, while there were no significant differences in the area under effect–time curve from 0 to 24 h after administration (AUEC0–24 h) and the area under effect–time curve from 0 to infinity (AUEC0−∞). The value of the rate constant of equilibration between plasma and the effect-site (ke0) 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.