Accumulation kinetics of propranolol in the rat: comparison of Michaelis-Menten-mediated clearance and clearance changes consistent with the "altered enzyme hypothesis".

(+)-Propranolol was infused at two rates into the pyloric vein (a portal vein tributary) of 15 male Sprague Dawley rats until apparent steady-state conditions were established (i.e., 8 hr at each rate). One group (n = 7) received the high dose (40 micrograms/min/kg) first, and in the other group (n = 8) the low dose (20 micrograms/kg/min) was used to initiate treatment. Free and total serum concentrations of propranolol were measured. When the low dose was given first, the apparent steady-state concentrations achieved during low- and high-rate infusion steps were 166 +/- 37 and 774 +/- 235 ng/mL, respectively. These data are consistent with a simple Michaelis-Menten kinetic model and the key parameters of such a model (Vmax and Km) were estimated. However, a crucial test of such a model (and one which should give insight regarding the relevance of an "altered enzyme hypothesis") is to reverse the order of infusion steps since, in a system controlled by Michaelis-Menten kinetics, the same steady-state concentrations should be achieved regardless of the order in which infusion steps are given. When the sequence of infusion rates was reversed, steady-state concentrations were 492 +/- 142 and 298 +/- 79 ng/mL for the high and low infusion rates, respectively. Clearly, a history of high-dose exposure reduces the intrinsic clearance of total drug (CLss) during a subsequent low-dose exposure (i.e., the apparent steady-state levels during the low-dose pyloric vein infusions were significantly different; P < 0.001). When these data were corrected for plasma protein binding, the same trends emerged.(ABSTRACT TRUNCATED AT 250 WORDS)