A possible mechanism of the impairment of hepatic microsomal monooxygenase activities after multiple administration of propranolol in rats.

The mechanism of selective inhibition of propranolol hydroxylations after multiple administration of the drug was investigated by metabolic inhibition studies in rat liver microsomes. The time course of irreversible binding of a reactive metabolic intermediate(s) of propranolol to liver microsomal protein, which was proposed as the cause of the impairment of enzymatic activities, had a delayed phase followed by a rapid linear rise, while the unmetabolized propranolol remaining in the reaction mixture showed a rapid linear decrease immediately after the onset of incubation. Thus, it was conceivable that the reactive intermediate(s) was not always formed directly from the parent drug, propranolol. Among four primary metabolites of propranolol, 4-hydroxypropranolol was the most potent inhibitor of propranolol hydroxylase activities, and this inhibition was much enhanced by preincubation of 4-hydroxypropranolol with NADPH. The type of inhibition kinetics of propranolol 5- and 7-hydroxylase activities by 4-hydroxypropranolol was changed from a competitive type to a non-competitive type by the preincubation. These results suggest that a reactive metabolite(s) of propranolol which impaired propranolol hydroxylase activities is a further metabolite(s) of 4-hydroxypropranolol.