The effect of age on diurnal variation in the pharmacokinetics of propranolol in hypertensive subjects

Abstract

There is diurnal variation in the absorption rate of propranolol in younger subjects. This study was undertaken to examine the effect of age on the chronopharmacokinetics of propranolol. We gave 20 mg of propranolol orally to 13 younger and 11 older hypertensive subjects at 09.00 h (day study) or 21.00 h (night study) in a cross-over design. Plasma concentrations of propranolol and its metabolites, 4-hydroxypropranolol and naphthoxylactic acid, were determined just before and at 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 h after dosage. In the younger subjects the absorption rate constant (k_a) of propranolol and its maximum plasma concentration (C_max) were significantly higher and the time to maximum concentration (t_max) was significantly shorter in the day than at night. There were similar time-variant changes in C_max and t_max for 4-hydroxypropranolol and naphthoxylactic acid. In contrast, there were no time-variant changes in k_a, C_max and t_max of propranolol and its metabolites in the older subjects. These results suggest that propranolol is absorbed more rapidly after morning dosing than after night-time dosing in younger but not in older subjects. Based on these findings, we speculate that the time-variance in the absorption rate or first-pass elimination, or both, of propranolol diminish with age.