Circadian bioavailability and some effects of propranolol in healthy subjects and in liver cirrhosis.

The aim of the study was to establish whether and how circadian rhythms alter the bioavailability of, and response of circulatory and ventilatory functions to 80 mg of propranolol given at four different test times. Both Cmax and AUC were lowest at 2:00 pm as compared with other test times in healthy group (N = 6), lower in cirrhosis (N = 6), but none in portacaval shunt (N = 3). Thus, at 2:00 pm, liver extraction seems to be the best in healthy subjects, worse in cirrhotics and negligible in PC shunt. The mean AUC value in PC shunt patients was three times as high as in healthy subjects and cirrhotics. This seems to be due to the reduced first-pass extraction phenomenon in the liver in PC cases. All subjects exhibited a prompt and significant depression of radial pulse and systolic BP; this effect on radial pulse was lasting longer at 2:00 am than at other test times. The initial values of PEF were lowest at 2:00 am and no depressing effect of propranolol was observed in comparison with other test times. From the practical point of view, the changeable bioavailability of propranolol given at different times of the day has no direct consequences in regards to the temporal response to the drug in healthy subjects and cirrhotics, since it is likely that both propranolol and its metabolites (4-OHP) are active as beta-blockers. Twenty-four hour oscillations of the responses to propranolol seem to exist both in healthy and cirrhotic patients.