Pharmacokinetic and pharmacodynamic modelling of atenolol in rabbits maintained on continuous peritoneal dialysis

Abstract

The pharmacokinetic and pharmacodynamic profiles of atenolol were studied in adult male rabbits on continuous peritoneal dialysis given 3 mg/kg i.v. before and during renal failure. The average terminal elimination half-life for the drug was 2.5 h calculated from blood, dialysate or urinary data. This value increased about nine times in anuric conditions. Although atenolol was eliminated in the peritoneal fluid, the amount excreted was relatively low both in normal conditions and renal failure, respectively 0.6 and 7% of the administered dose. The pharmacokinetic model was extended by an "effect compartment", which has no influence on the predetermined mass of drug in the body, to analyse the relationship between heart rate fall and changes in atenolol blood concentrations. After drug administration, heart rate fell rapidly about 90 beats in both states. The mean equilibration half-time of atenolol effect and blood concentrations was 0.7 and 1.5 h in normal and pathological states, respectively. The mean blood concentration required to produce 50% of heart rate fall was similar in both conditions, 0.23 mg/l. The nine-fold decrease of atenolol elimination in anuria was in good agreement with the increase in duration of the drug's effect, and was suitably described by the "effect model".

PK/PD Modeling of β-Blockers in Cardiovascular Disease: An Update

“…As expected, anuria was associated with a ninefold decrease of atenolol elimination and a prolongation of drug effect during anuria [43]. Nevertheless, by using an effect compartmental model, the authors did not found differences in main PK/PD parameters, E max and EC 50 , of atenolol chronotropic effect comparing rabbits before and during renal failure [43].…”

“…Nevertheless, by using an effect compartmental model, the authors did not found differences in main PK/PD parameters, E max and EC 50 , of atenolol chronotropic effect comparing rabbits before and during renal failure [43]. These results suggest that reduction of kidney function alters atenolol PK properties without affecting their PD profile [43]. In rabbits with experimental liver failure, Bortolloti et al [44] have evaluated the impact of liver injury on PK/PD properties of metoprolol, a lipophilic second-generation β-blocker that undergoes extensive biotransformation.…”

“…For instance, as atenolol is a second-generation β-blocker with predominantly renal elimination, Celardo et al [43] have assessed the influence of renal failure on the PK and PD profiles of atenolol in adult male rabbits on continuous peritoneal dialysis. As expected, anuria was associated with a ninefold decrease of atenolol elimination and a prolongation of drug effect during anuria [43].…”

“…Influence of renal function on PK/PD properties of atenolol Impact of live injury on PK/PD properties of metoprolol Influence of protein binding on chronotropic effect of S-propranolol Relevance of sympathetic overactivity in the maintenance of hypertension Contribution of sympatholytic activity of carvedilol on antihypertensive response Characterization of sustained-release formulations of atenolol [43].…”

Models for evaluating the pharmacokinetics and pharmacodynamics for β-blockers

“…By using an effect-compartment model, Celardo et al [72] evaluated the influence of renal failure on the PK and PD profiles of atenolol in adult male rabbits on continuous peritoneal dialysis. The authors reported a ninefold decrease of atenolol elimination and an increase in duration of drug effect during anuria [72].…”