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 meta bolism was investigated in the rat. V(max) values of the high-affinity phase for biphasic kinetics of propranolol 4- and 5-hydroxylase activ ities were decreased by propranolol pretreatment, while those of the l ow-affinity phase were unchanged. The V(max) value of monophasic 7-hyd roxylase activity was also decreased. On the other hand, the V(max) va lue of N-desisopropylase activity in the propranolol-treated rats was increased more than 2-fold compared with non-treated (control) rats, r esulting in a change from monophasic in control rats to biphasic kinet ics in propranolol-treated rats. These findings indicate that repetiti ve administration of propranolol selectively impairs a CYP2D isozyme t hat is involved in the high-affinity phases for propranolol ring-hydro xylations.