Steady-state disposition of propranolol and its total metabolites in the spontaneously hypertensive rat: chronic subcutaneous vs. intracerebroventricular infusion with osmotic minipumps.

The steady-state disposition of propranolol and its total metabolites was measured after 6 day continuous subcutaneous (1 mg/kg/day) or intracerebroventricular (i.c.v., 0.01 and 1 mg/kg/day) infusion of dl-[3H]propranolol with osmotic minipumps in spontaneously hypertensive rats. After 2 days daily excretion of total radioactivity was 70% or more of the total dose infused each day. Steady-state plasma concentrations (day 3 and 6) of propranolol and its total metabolites did not differ significantly during subcutaneous or i.c.v. infusion of 1 mg/kg/day. During i.c.v. infusion with 0.01 mg/kg/day these concentrations were only 0.01 to 0.02 times as high. Propranolol and its total metabolite concentrations did not differ significantly in peripheral tissues during subcutaneous or i.c.v. infusion of 1 mg/kg/day, whereas brain propranolol concentrations were 40- to 600-fold higher during i.c.v. infusion. During i.c.v. infusion with 0.001 mg/kg/day, peripheral propranolol and total metabolite concentrations were only 0.003 to 0.02 times those following 1 mg/kg/day. Brain propranolol concentrations after 0.01 mg/kg/day i.c.v. were in the same range as those following 1 mg/kg/day subcutaneously. The data suggest that the osmotic minipump is a useful tool for creating and maintaining a steady-state for propranolol in spontaneously hypertensive rats. Moreover, by i.c.v. placement of the pump outlet the brain can be selectively perfused with this agent for a prolonged period of time.