Kinetic analysis of propranolol-induced impairment of its own metabolism in rats.

The effect of repetitive oral administration of propranolol (100 mg kg-1 day-1, 5 days) on the kinetics of liver microsomal propranolol metabolism was investigated in the rat. V(max) values of the high-affinity phase for biphasic kinetics of propranolol 4- and 5-hydroxylase activities were decreased by propranolol pretreatment, while those of the low-affinity phase were unchanged. The V(max) value of monophasic 7-hydroxylase activity was also decreased. On the other hand, the V(max) value of N-desisopropylase activity in the propranolol-treated rats was increased more than 2-fold compared with non-treated (control) rats, resulting in a change from monophasic in control rats to biphasic kinetics in propranolol-treated rats. These findings indicate that repetitive administration of propranolol selectively impairs a CYP2D isozyme that is involved in the high-affinity phases for propranolol ring-hydroxylations.