THE INHIBITORY EFFECT OF PROPRANOLOL PRETREATMENT ON ITS OWN METABOLISM IN THE RAT

  • 1 January 1981
    • journal article
    • research article
    • Vol. 218  (3) , 575-581
Abstract
Repetitive oral administration of propranolol to rats (100 mg/kg/day for 5 days) inhibited hepatic microsomal propranolol metabolism when incubated at low initial substrate concentrations (< 2 .mu.M). Associated with the inhibition of propranolol metabolism was a significant reduction in metabolites derived from naphthalene ring oxidation and an increased formation of N-desisopropylpropranolol. In vivo propranolol pretreatment increased hepatic concentration and systemic availability of propranolol; decreased hepatic and plasma concentration of polar metabolites and increased plasma concentration of metabolites derived from propranolol N-dealkylation. Propranolol was converted both in vitro and in vivo by a hepatic microsomal mixed-function oxidase to a reactive metabolite capable of covalently binding with microsomal macromolecules. Selective covalent binding of the reactive intermediate to the molecular form of cytochrome P-450 that ring hydroxylates propranolol would account for the marked inhibition of propranolol metabolism in vitro and for the increased systemic availability of propranolol in vivo after pretreatment.