The duration and extent of cardiac beta-blockade and their relationship to propranolol pharmacokinetics were assessed in nine healthy volunteers. Each subject received 160 mg of regular propranolol (R), 160 mg of sustained-release propranolol (SR) and no drug (control), both as single doses and once daily for 7 days. After single doses and at steady-state, both products caused a decrease in exercise heart rate for at least 24 h, compared to control. The time course of effect was similar to the time course of serum propranolol concentration. The oral clearance of propranolol decreased from single doses to steady-state for both R and SR; however, the difference achieved statistical significance only for R. These changes were reflected in mean accumulation ratios (AUC steady-state 0-24 h/AUC single dose 0-infinity) of 1.49 and 1.68 for R and SR, respectively. The pharmacokinetic data are consistent with a decrease in intrinsic hepatic clearance of propranolol, leading to an increase in bioavailability at steady-state. Despite a two-fold difference in the bioavailability of R and SR, there was no difference in the area under the effect-time curve at steady-state.
The accumulation of (+)-and (-)-propranolol was investigated in nine subjects who received 160 mg of racemic propranolol as a single dose and then once daily for 7 days. The serum concentrations of propranolol enantiomers were measured by h.p.l.c. using a novel chiral stationary phase allowing direct resolution of underivatized propranolol. The (+)-propranolol AUC increased from 412 ± 223 ng ml-' h after single doses (0-(}) to 584 + 279 ng ml-' h at steady-state (0-24 h) (P < 0.05). Similarly, (-)-propranolol AUC increased from 609 ± 304 to 777 ± 370 ng ml-1 h (P < 0.05). The AUC ratio (-)/(+) was 1.52 ± 0.36 and 1.32 ± 0.17 after single doses and steady-state, respectively (P > 0.05). Therefore, nonlinear accumulation occurs with both enantiomers although there is a trend for the (-)/(+) ratio to decrease at steady-state.
Theophylline and subcutaneous terbutaline are frequently used concurrently in the management of acute asthma. Recent evidence demonstrating a reduction in theophylline serum concentrations during concomitant oral terbutaline therapy prompted our evaluation of subcutaneous terbutaline's effect on theophylline pharmacokinetics. Using a randomized, placebo controlled, crossover design, the disposition of a single oral theophylline dose (7 mg/kg) was studied in eight healthy, adult males before and after repeated subcutaneous administration of terbutaline (0.25 mg). Two-way analysis of variance revealed no significant difference in elimination rate constant (ke), area under the concentration-time curve (AUC), or apparent oral clearance (CL/F) of theophylline following terbutaline administration. These results indicate that subcutaneous administration of terbutaline does not alter the pharmacokinetics of single, oral doses of theophylline in adults.
The effects of 7 days of pretreatment with atenolol, 150 mg day-1, or nadolol, 80 mg day-', on the pharmacokinetics and metabolism of theophylline were determined in six male smokers. Theophylline clearance, volume of distribution, half-life and the urinary excretion of theophylline and its metabolites were unchanged during either treatment compared with control.
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