Age-dependence in capacity-limited uptake kinetics of propranolol by isolated rat hepatocytes

Overall initial uptake rates of propranolol by isolated rat hepatocytes were analyzed to give both apparently linear and saturable processes. The rate constant for the linear transport process in 7- and 24-week old rats was approximately 0.01 ml X sec-1 X (10(6) cells)-1. For the capacity-limited uptake process of propranolol, the kinetic parameters in 7-week-old rats, were estimated as Vmax = 0.609 microgram X (10(6) cells)-1 X sec-1 and Km = 8.17 micrograms/ml, whereas in 24-week-old rats, Vmax = 0.348 microgram X (10(6) cells)-1 X sec-1 and Km = 9.40 micrograms/ml. The overall uptake rate, when the hepatocytes were incubated with 20 micrograms/ml of propranolol, was reduced with age of the rats between 5 or 7 and 24 weeks and declined gradually thereafter, A higher cell to medium concentration ratio for the initially, net transported component of propranolol in relatively young (5- to 11-week-old) rats suggested an age-dependent saturable uptake process. This was supported by the direct comparison of the saturable uptake rates between 7 and 24 weeks. Therefore, the saturable sinusoidal transport (i.e. saturable uptake by the hepatocytes) may be considered one of the most important mechanisms determining the age-dependence in the intrinsic hepatic clearance of this drug noted in our previous report.