Kinetic analysis of propranolol‐induced impairment of its own metabolism in rats

Abstract— 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. 1994 Royal Pharmaceutical Society of Great Britain